Статті в журналах: "Exosomes, myeloid cells, tumor, PDAC"

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Lucotti, Serena, Yusuke Ogitani, Candia M. Kenific, Linda Bojmar, Michele Cioffi, Pernille Lauritzen, Henrik Molina, et al. "Abstract 3138: The lung pro-thrombotic niche drives cancer-associated thromboembolism via exosomal ITGB2." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3138. http://dx.doi.org/10.1158/1538-7445.am2022-3138.

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Abstract Thromboembolism (TE) is a common complication in cancer patients and the second leading cause of cancer-related deaths. The incidence of TE varies in different cancer types, with the highest risk in lung cancer and pancreatic ductal adenocarcinoma (PDAC), and in advanced-stage and metastatic cancers. Despite the benefits associated with thromboprophylaxis for symptomatic TE, the prevention of TE still remains an unmet clinical need due to lack of biomarkers predictive of TE risk and the bleeding risk associated with the routine use of anti-coagulants. Exosomes are small circulating extracellular vesicles that mediate cell-to-cell communication. Cancer cells and the tumor microenvironment release large numbers of exosomes into the blood circulation and have displayed a therapeutic and predictive value in systemic diseases. Integrins expressed on the surface of exosomes drive their selective organotropism and prepare distant sites for metastatic seeding by establishing favorable pre-metastatic niches. Here we show that exosomes from metastasis-bearing lungs or pre-metastatic lungs of mice with melanoma, breast, lung and pancreatic cancer induce TE in mice and express high levels of integrin beta 2 (ITGB2). Instead, exosomes from tumor cell lines, primary tumors or other metastasis-bearing organs did not show any pro-thrombotic properties. Myeloid cells including monocytes/macrophages and neutrophils infiltrating pre- and post-metastatic lungs were the main source of ITGB2+ pro-thrombotic exosomes. Blockade of ITGB2 on lung-derived exosomes, or systemically in mice, prevented exosome-induced platelet aggregation and TE, and reduced metastasis. Examination of the mechanisms of ITGB2-induced TE showed that exosomal ITGB2 interact directly or through fibrin with different binding partners on platelets, and induce their activation and aggregation. Importantly, we found that exosomal ITGB2 levels are elevated in the plasma of PDAC patients prior to TE events in comparison to PDAC patients with no history of TE, and thus might serve as prognostic biomarker of TE. Together, our results provide the first evidence of the establishment of a pro-thrombotic lung niche in different cancer types. Moreover, we identify exosomal ITGB2 as a new target for the prevention and/or treatment of TE, as well as a potential “liquid biopsy” analyte for the early stratification of patients at high risk of TE. Citation Format: Serena Lucotti, Yusuke Ogitani, Candia M. Kenific, Linda Bojmar, Michele Cioffi, Pernille Lauritzen, Henrik Molina, Soren Heissel, Harry B. Lengel, Xiaohong Jing, Haiying Zhang, Irina Matei, Eileen M. O'Reilly, William R. Jarnagin, David R. Jones, James B. Bussel, David Kelsen, Jacqueline F. Bromberg, Diane M. Simeone, David Lyden. The lung pro-thrombotic niche drives cancer-associated thromboembolism via exosomal ITGB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3138.

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Padoan, Andrea, Mario Plebani, and Daniela Basso. "Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity." International Journal of Molecular Sciences 20, no. 3 (February 5, 2019): 676. http://dx.doi.org/10.3390/ijms20030676.

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Systemic and local chronic inflammation might enhance the risk of pancreatic ductal adenocarcinoma (PDAC), and PDAC-associated inflammatory infiltrate in the tumor microenvironment concurs in enhancing tumor growth and metastasis. Inflammation is closely correlated with immunity, the same immune cell populations contributing to both inflammation and immune response. In the PDAC microenvironment, the inflammatory cell infiltrate is unbalanced towards an immunosuppressive phenotype, with a prevalence of myeloid derived suppressor cells (MDSC), M2 polarized macrophages, and Treg, over M1 macrophages, dendritic cells, and effector CD4+ and CD8+ T lymphocytes. The dynamic and continuously evolving cross-talk between inflammatory and cancer cells might be direct and contact-dependent, but it is mainly mediated by soluble and exosomes-carried cytokines. Among these, tumor necrosis factor alpha (TNFα) plays a relevant role in enhancing cancer risk, cancer growth, and cancer-associated cachexia. In this review, we describe the inflammatory cell types, the cytokines, and the mechanisms underlying PDAC risk, growth, and progression, with particular attention on TNFα, also in the light of the potential risks or benefits associated with anti-TNFα treatments.

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Wu, Guo, Xiaojie Ding, Gang Quan, Jianwei Xiong, Qiang Li, Zhonghu Li, and Yaqin Wang. "Hypoxia-Induced miR-210 Promotes Endothelial Cell Permeability and Angiogenesis via Exosomes in Pancreatic Ductal Adenocarcinoma." Biochemistry Research International 2022 (November 25, 2022): 1–13. http://dx.doi.org/10.1155/2022/7752277.

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Background. Exosomes have been proven to play important diagnostic, regulatory, or communication roles in tumorigenesis, tumor progression, or metastasis; in recent studies, lots of molecules, including miRNAs, were found to be aberrantly expressed in tumor exosomes and were correlated with tumor development. However, studies about the expression, relationship, or control mechanisms of miRNAs in exosomes in pancreatic ductal adenocarcinoma (PDAC) are scarce and urgently needed. The aim of this article was to identify and investigate abnormally expressed miRNAs in PDAC exosomes in vivo and in vitro. Methods. Microarray studies were used to detect aberrantly expressed miRNAs in PDAC exosomes, and miR-210 expression in cells or exosomes was further analyzed by qRT-PCR. Bioinformatics analyses, dual-luciferase assays, WB, and other assays were utilized to explore the miRNA molecular mechanisms. The living cell coculture model and immunofluorescence analysis were employed to image the communication between PDAC cells and endothelial cells. Other biological experiments in the study include a real-time intravital imaging system, EdU, transwell, xenograft models, and so on. Results. miR-210 is significantly expressed in PDAC exosomes and malignant cells. High miR-210 significantly facilitated tumor angiogenesis, cell invasion, and proliferation in PDAC cells. Further mechanistic detection revealed that miR-210 negatively regulated EFNA3 expression and participated in the PI3K/AKT/VEGFA or Wnt/Β-catenin/RHOA pathways, thus promoting tumor angiogenesis and cellular permeability. PDAC cells promote endothelial angiogenesis or permeability via miR-210 transmission by tumor exosomes. Exosomal miR-210 promotes PDAC progression in vivo. Further detection of PDAC plasma exosomal miR-210 suggests that exosomal miR-210 expression was high and significantly associated with vascular invasion and TNM stage and was an independent risk factor for PDAC overall survival. Conclusions. PDAC cell-secreted exosomes could promote angiogenesis and cellular permeability of neighboring endothelial angiogenesis or permeability via miR-210 transmission. Exosomal miR-210 may play important roles in tumor biology and may be a useful prognostic marker in PDAC.

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Li, Zhonghu, Yang Tao, Xiaoya Wang, Peng Jiang, Jie Li, Minjie Peng, Xi Zhang, et al. "Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer." Cellular Physiology and Biochemistry 51, no. 2 (2018): 610–29. http://dx.doi.org/10.1159/000495281.

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Background/Aims: MicroRNAs (miRNAs) or exosomes have recently been shown to play vital regulatory or communication roles in cancer biology. However, the roles and mechanisms of exosomal miRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. We aimed to investigate the detailed roles and mechanisms of tumor-generated exosomal miRNAs in progression of PDAC. Methods: miR-222 was identified by miRNA microarray studies in exosomes of PDAC cells, and further analyzed in plasma exosomes of PDAC patients. The regulatory mechanisms of miR-222 were explored by qRT-PCR, WB, dual-luciferase assays and immunofluorescence or confocal analysis. Other biological assays include transwell, xenograft models and so on. Results: miR-222 is significantly high in tumor exosomes or highly invasive PDAC cells. miR-222 could directly regulate p27 to promote cell invasion and proliferation. miR-222 could also activate AKT by inhibiting PPP2R2A expression, thus inducing p27 phosphorylation and cytoplasmic p27 expression to promote cell survival, invasion and metastasis. Expressions of miR-222 and p27 were significantly inversely correlated, and cytoplasmic p27, instead of nuclear p27, was associated with tumor malignancy. miR-222 could be transmitted between PDAC cells via exosome communication, and the exosomal miR-222 communication is functional. Plasma exosomal miR-222 in PDAC patients was high and significantly correlated to tumor size and TNM stage, and was an independent risk factor for PDAC patient survival. Conclusion: Tumor-generated exosomes could promote invasion and proliferation of neighboring tumor cells via miR-222 transmission, the plasma exosomal miR-222 plays important roles and may be a useful prognostic maker in PDAC.

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Batista, Ines, and Sonia Melo. "Exosomes and the Future of Immunotherapy in Pancreatic Cancer." International Journal of Molecular Sciences 20, no. 3 (January 29, 2019): 567. http://dx.doi.org/10.3390/ijms20030567.

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Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, associated with a late diagnosis and a five-year survival rate of 8%. Currently available treatments fall short in improving the survival and quality of life of PDAC patients. The only possible curative option is still the surgical resection of the tumor. Exosomes are extracellular vesicles secreted by cells that transport proteins, lipids, and nucleic acids to other cells, triggering phenotypic changes in the recipient cells. Tumor cells often secrete increased amounts of exosomes. Tumor exosomes are now accepted as important players in the remodeling of PDAC tumor stroma, particularly in the establishment of an immunosuppressive microenvironment. This has sparked the interest in their usefulness as mediators of immunomodulatory effects for the treatment of PDAC. In fact, exosomes are now under study to understand their potential as nanocarriers to stimulate an immune response against cancer. This review highlights the latest findings regarding the function of exosomes in tumor-driven immunomodulation, and the challenges and advantages associated with the use of these vesicles to potentiate immunotherapy in PDAC.

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Chu, Xiangyu, Yinmo Yang, and Xiaodong Tian. "Crosstalk between Pancreatic Cancer Cells and Cancer-Associated Fibroblasts in the Tumor Microenvironment Mediated by Exosomal MicroRNAs." International Journal of Molecular Sciences 23, no. 17 (August 23, 2022): 9512. http://dx.doi.org/10.3390/ijms23179512.

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant digestive tumors, characterized by a low rate of early diagnosis, strong invasiveness, and early metastasis. The abundant stromal cells, dense extracellular matrix, and lack of blood supply in PDAC limit the penetration of chemotherapeutic drugs, resulting in poor efficacy of the current treatment regimens. Cancer-associated fibroblasts (CAFs) are the major stromal cells in the tumor microenvironment. Tumor cells can secrete exosomes to promote the generation of activated CAFs, meanwhile exosomes secreted by CAFs help promote tumor progression. The aberrant expression of miRNAs in exosomes is involved in the interaction between tumor cells and CAFs, which provides the possibility for the application of exosomal miRNAs in the diagnosis and treatment of PDAC. The current article reviews the mechanism of exosomal miRNAs in the crosstalk between PDAC cells and CAFs in the tumor microenvironment, in order to improve the understanding of TME regulation and provide evidence for designing diagnostic and therapeutic targets against exosome miRNA in human PDAC.

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Richards, Katherine E., Weikun Xiao, and Reginald Hill. "Cancer-Associated Fibroblasts Confer Gemcitabine Resistance to Pancreatic Cancer Cells through PTEN-Targeting miRNAs in Exosomes." Cancers 14, no. 11 (June 6, 2022): 2812. http://dx.doi.org/10.3390/cancers14112812.

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Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death in the United States. Even though the poor prognosis of PDAC is often attributed to late diagnosis, patients with an early diagnosis who undergo tumor resection and adjuvant chemotherapy still show tumor recurrence, highlighting a need to develop therapies which can overcome chemoresistance. Chemoresistance has been linked to the high expression of microRNAs (miRs), such as miR-21, within tumor cells. Tumor cells can collect miRs through the uptake of miR-containing lipid extracellular vesicles called exosomes. These exosomes are secreted in high numbers from cancer-associated fibroblasts (CAFs) within the tumor microenvironment during gemcitabine treatment and can contribute to cell proliferation and chemoresistance. Here, we show a novel mechanism in which CAF-derived exosomes may promote proliferation and chemoresistance, in part, through suppression of the tumor suppressor PTEN. We identified five microRNAs: miR-21, miR-181a, miR-221, miR-222, and miR-92a, that significantly increased in number within the CAF exosomes secreted during gemcitabine treatment which target PTEN. Furthermore, we found that CAF exosomes suppressed PTEN expression in vitro and that treatment with the exosome inhibitor GW4869 blocked PTEN suppression in vivo. Collectively, these findings highlight a mechanism through which the PTEN expression loss, often seen in PDAC, may be attained and lend support to investigations into the use of exosome inhibitors as potential therapeutics to improve the effectiveness of chemotherapy.

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YU, Shaohua, cunren Liu, Jianhua Wang, yuelong Liu, liming Zhang, Yingzi Cong, william Grizzle, and huang-Ge Zhang. "Tumor exosomes inhibit differentiation of bone marrow dendritic cells (49.14)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S85. http://dx.doi.org/10.4049/jimmunol.178.supp.49.14.

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Abstract The production of exosomes by tumor cells has been implicated in tumor-associated immune suppression. Here we show that, in mice, exosomes produced by TS/A murine mammary tumor cells target CD11b+Gr-1+ myeloid precursors in the bone marrow in vivo and that this is associated with an accumulation of myeloid precursors in the spleen. Moreover, we demonstrate that TS/A exosomes block differentiation of murine myeloid precursor cells into dendritic cells in vitro. Addition of tumor exosomes at day 0 led to a complete block of differentiation into dendritic cells, whereas addition at later time points was less effective. Similarly, exosomes produced by human breast tumor cells inhibited differentiation of human monocytes in vitro. The levels of IL-6 and phosphorylated Stat3 were elevated 12 h after tumor exosome stimulation of murine myeloid precursors, and tumor exosomes were less effective in inhibiting differentiation of bone marrow cells isolated from IL-6 knockout mice. These data suggest that tumor exosome-mediated induction of IL-6 plays a role in blocking bone marrow dendritic cell differentiation.

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Kulkarni, Prateek, Reetobrata Basu, and John J. Kopchick. "Effects of Growth Hormone on Pancreatic Cancer Derived Exosomes." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A1016—A1017. http://dx.doi.org/10.1210/jendso/bvab048.2079.

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Abstract In 2020, the National Cancer Institute (NCI) estimates 57,600 new cases and 47,050 deaths in the US due to pancreatic ductal adenocarcinoma (PDAC). A dismal 10% five-year overall survival rate in PDAC is attributed to late diagnosis, limited treatment options, a remarkably high metastasis rate, and resistance of this cancer to available therapies. Therefore, a better understanding of the mechanisms of how PDAC tumors acquire drug resistance and spread to distal parts of the body are necessary for developing novel therapeutic approaches. Exosomes, microscopic vesicles released from most cells (both tumor and non-tumor) have been recently established to play a significant role in cell to cell communication. Exosomes modulate their target cell responses systematically depending on the nature of exosomal cargoes (nucleic acids, proteins, and lipids). PDAC derived exosomes have been implicated to promote metastasis via forming a pre-metastatic niche of cells as well as enhancing drug resistance. Growth hormone (GH) secreted primarily by the pituitary gland promotes metastasis and drug resistance as shown by plethora of studies. No study has directly assessed the effect of GH on exosomal cargoes in terms of promoting metastases and drug resistance. In this report, we show that GH modulates various pancreatic cancer cell exosomal cargoes which in turn potentially amplifies tumor invasion and metastases. Our data shows that GH treatment on human and mouse PDAC cells increases the exosomal protein levels of TGFβ - a critical inducer of epithelial-to-mesenchymal transition (EMT, a process leading to metastasis). In addition, GH treatment also increases extracellular matrix-degrading enzymes, MMP2 and 9, as well as multi-drug efflux pump ABCC1, ABCB1, and ABCG2 in PDAC cells. These results strongly implicate GH action in driving EMT and chemoresistance via exosomes in pancreatic cancer. Exosomes have a crucial impact especially in the areas of diagnostics and therapeutics. This report is the first to show that GH modulates the effects of exosomes secreted by pancreatic cancer cells. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.

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Hasselluhn, Marie C., Lukas J. Vlahos, Dafydd Thomas, Alvaro Curiel Garcia, Amanda R. Decker, Tanner C. Dalton, Stephen A. Sastra, Carmine F. Palermo, Andrea Califano, and Kenneth P. Olive. "Abstract C032: Combination CAF/myeloid targeting in PDAC." Cancer Research 82, no. 22_Supplement (November 15, 2022): C032. http://dx.doi.org/10.1158/1538-7445.panca22-c032.

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Abstract Immunotherapy has revolutionized clinical care for many cancers, yet these treatments fail to control disease in many patients and new strategies are needed to improve anti-tumor immunity and enhance response rates. There is great need for an increased understanding of the cellular crosstalk within tumors and the identification of stromal and immune populations involved in shaping the tumor microenvironment (TME). Local immunosuppression (LIS) is one of the striking hallmarks of Pancreatic Ductal Adenocarcinoma (PDAC), a disease that is highly resistant to existing immunotherapies. Oncogenic Kras activation in tumor cells promotes the invasion and proliferation of tumor-supporting stromal cells, while excluding cancer-targeted cytotoxic T cells. LIS is mediated by multiple subtypes of cancer-associated fibroblasts (CAFs) and myeloid cells resident within the tumor parenchyma. Multiple prior attempts to reverse LIS in PDAC by targeting individual stromal cell populations have been unsuccessful, alluding to the complexity of stromal crosstalk within the TME. The stromal diversity of PDAC complicates investigating paracrine cascades involving multiple cell types. To decipher diverse drug effects on altering the TME, we employ in vivo studies in mouse models recapitulating the human disease, as well as a novel tumor explant model that enables the short-term culture of intact human or murine PDAC. Importantly, PDAC explants maintain their histopathological architecture and cellular diversity over time. This medium-throughput platform allows for testing of multiple drugs and mechanistic hypotheses in the native PDAC TME. We show in preliminary data that Smoothened inhibition (SMOi) decreases proliferation and activity of myCAFs, but provokes the expansion of CD11b-positive myeloid cells in vivo. Thus, we hypothesize that LIS in PDAC is maintained by a delicate balance between myCAFs and myeloid cells, preventing effective T cell invasion. Single cell RNA-seq data comparing ctrl vs. SMOi-treated murine PDAC elucidates stromal subpopulations involved in the LIS phenotype and guides the identification of myeloid subtypes emerging after SMOi. Strikingly, we demonstrated that simultaneous SMOi and targeting myeloid cells via anti-Gr1 or CCR1 inhibition (CCR1i) significantly elevates cytotoxic T cell numbers within the TME. We are currently investigating whether the activity of these T cells may be further potentiated through combination with immunomodulatory agents. By testing various treatment combination in the same TME, we will identify the best synergistic effects for future immunotherapy approaches in human PDAC. In summary, we are elucidating the complex mechanism behind LIS in PDAC by employing our novel explant culture system alongside in vivo studies. We aim to develop a translatable regimen to neutralize LIS, reactivating the cytotoxic T cells in the tumor periphery to invade, proliferate, and attack cancer cells. Citation Format: Marie C. Hasselluhn, Lukas J. Vlahos, Dafydd Thomas, Alvaro Curiel Garcia, Amanda R. Decker, Tanner C. Dalton, Stephen A. Sastra, Carmine F. Palermo, Andrea Califano, Kenneth P. Olive. Combination CAF/myeloid targeting in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C032.

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Parkhideh, S., M. Mehdizadeh, A. Hajifathali, H. G. Nazari, E. Roshandel, and R. Mirfakhraie. "Exosomes derived from chronic myeloid leukemia cells: roles in disease progression, survival, and treatment." Pakistan Journal of Medical and Health Sciences 15, no. 5 (May 30, 2021): 1533–39. http://dx.doi.org/10.53350/pjmhs211551533.

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Exosomes, biologically active extracellular vesicles, are derived from normal and neoplastic cells. Emerging evidence revealed that exosomes modulate cell-cell communication and involve in hemostatic and pathologic processes. Recent studies have shown that exosomes released from cancer cells such as chronic myeloid leukemia cells could act as a key mediator in tumor induction and progression. Myeloid cells-derived exosomes affect different processes including angiogenesis, neoplastic proliferation, tumor cell survival, and imatinib resistance. These exosomes induce angiogenesis and tumor progression by IL-8 overexpression in both leukemic and bone marrow stromal cells. Exosomes cargo could alter the expression of different adhesion molecules, anti-and pro-apoptotic molecules, cytokines, and chemokines such as VCAM-1, ICAM-1, BCL, BAD, BAX, TGF-β, TNF-α, CXCL12 which affect tumor migration, homing, survival, and growth. CML-derived exosomes can also regulate signal transduction pathways, such as ERK/MAPK, ERK/Akt, EGFR/Ras, and Wnt. Furthermore, they can be applied as a vehicle for drug delivery or sensitization of drug-resistant cells. Here, we reviewed the role of chronic myeloid cell-derived exosomes in tumor growth, survival, and resistance to treatment. Keywords: Chronic myeloid leukemia, Exosome, Angiogenesis, Tyrosine kinase inhibitor, Drug resistance

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Thyagarajan, Anita, Mamdouh Salman A. Alshehri, Kelly L. R. Miller, Catherine M. Sherwin, Jeffrey B. Travers, and Ravi P. Sahu. "Myeloid-Derived Suppressor Cells and Pancreatic Cancer: Implications in Novel Therapeutic Approaches." Cancers 11, no. 11 (October 24, 2019): 1627. http://dx.doi.org/10.3390/cancers11111627.

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Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

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Xiao, Weikun, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, and Reginald Hill. "Abstract 1567: Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1567. http://dx.doi.org/10.1158/1538-7445.am2022-1567.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of cancer with few effective treatments. Despite recent advances in in other cancers, the five-year survival rate of PDAC is still only 10%, with most patients succumbing to their disease within the first year. One of the main factors responsible for this poor outcome is the development of chemoresistance in nearly all clinical cases. While the intrinsic factors that facilitate chemoresistance in the tumor cells have been studied extensively, fewer studies have elucidated how the complex and unique microenvironment surrounding the tumor affects therapeutic responses. The abundant stromal cells and the stiff desmoplastic microenvironment constitute more than 90% of the primary tumor bulk. However, there is a lack of high-throughput, easily tunable models to recapitulate this complex microenvironment, in order to identify a critical cell-extrinsic factors that could drive acquired chemoresistance in PDAC cells. To address this issue, we have developed a Matrigel-based, orthogonally tunable 3-dimensional (3D) culture system to co-culture mouse derived PDAC organoids and host-matching cancer-associated fibroblasts (CAFs). Using this system, we found that matrix-activated CAFs readily remodel the desmoplastic matrix through lysol-oxidase dependent crosslinking. Moreover, our novel system demonstrates how collagen-I and matrix stiffness affect chemoresistance via the hypersecretion CAF-derived exosomes. Interestingly, our data show that it is CAF-derived exosomes, not the organoid-derived exosomes, that are most important in regulation of proliferation and chemoresistance. Lastly, we identified key cell surface integrins for collagen-I as therapeutic targets to prevent desmoplastic matrix-mediated chemo-resistance in PDAC. Our study provides insights into how matrix composition and stiffness affect therapeutic outcome in PDAC. Moving forward, therapies aimed at interrupting how PDAC cells and stomal cells sense the matrix microenvironment could be utilized to eventually overcome matrix-mediated chemoresistance in PDAC. Citation Format: Weikun Xiao, Chae-Young Eun, Xinyu Zhang, Charlene DeKalb, Mahsa Pahlavan, Bayan Mahgoub, Hanaa Knaneh, Alireza Sohrabi, Stephanie K. Seidlits, Reginald Hill. Increased extracellular matrix stiffness induces hypersecretion of chemoresistance-promoting cancer associated fibroblast-derived exosomes in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1567.

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Osipov, A., and L. Zheng. "P09.15 Targeting the stroma to enhance effector memory T cell infiltration and anti-tumor response to anti-PD1 antibody in pancreatic ductal adenocarcinoma." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A59.2—A60. http://dx.doi.org/10.1136/jitc-2020-itoc7.115.

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is resistant to immune checkpoint inhibition. One of the major resistance mechanisms is attributed to myeloid cells as an immunosuppressive element within the stroma of PDAC. It has been reported that focal adhesion kinase inhibitor (FAKi) can suppress immunosuppressive myeloid cells such as tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSC), consequently sensitizing tumor to anti-PD1 antibody in mouse models of PDAC. Our group has previously shown in a murine model that targeting the stroma via PEGylated recombinant human hyaluronidase (PEGPH20) enhanced the anti-tumor activity of the whole cell vaccine (GVAX) by targeting CXCR4-expressing myeloid cells and led to an increase in infiltration of CCR7- effector memory T cell subsets. Here, we evaluate the hypothesis that FAK expressing myeloid cell subsets modulate T cell infiltration in human PDAC and FAKi can synergize with PEGPH20 by targeting myeloid cells in PDAC.Material and MethodsResected human PDAC tissue specimens treated with GVAX and anti-PD1 therapy was used to assess FAK expression in myeloid cell subsets and its impact on T cell infiltration. A sequential staining and stripping multiplex IHC technique that incorporates 28 myeloid and lymphoid biomarkers, as well as phosphorylated FAK (pFAK) combined with computational image processing was used to assess myeloid cell populations, T cell infiltration and FAK expression.An established murine model of metastatic PDAC treated with and without anti-PD1 therapy was used to assess the synergy and immune-modulating effect of FAKi and stromal degradation of hyaluronan via PEGPH20.ResultsIn human PDAC, FAK is widely expressed in TAMs and neutrophils. Increased FAK expression is associated with increased CXCR4 expression. Lower pFAK density in neutrophils and M2 TAMs, but not lower pFAK density in M1 TAMs, is associated with higher CD8+ T cell infiltration.FAKi and combination of FAKi with anti-PD1 extends survival in the mouse metastasis model of PDAC. Adding PEGPH20 to FAKi and anti-PD1 antibody significantly prolonged survival in this model. Comparing to the combination of FAKi and anti-PD1 antibody, adding PEGPH20 significantly decreased the number of CXCR4-expressing myeloid cells in the tumor microenvironment (TME) of PDAC and consequently led to an increase in the amount of CCR7+ central memory T cells. Additionally, the amount of G-MDSCs, inflammatory resident monocytes and PDL1 expressing myeloid cells in the TME of PDAC, was also decreased in PDAC treated with the triple combination of PEGPH20, FAKi and anti-PD1 antibody compared to FAKi and anti-PD1 antibody.ConclusionFAK is widely expressed in myeloid cell populations, directly correlated with CXCR4 expression and decreased FAK expression in a myeloid (M2 TAMs, neutrophil) inflamed stroma is associated with infiltration of effector CD8 T cells in human PDAC. Stromal degradation of hyaluronan via PEGPH20 combined with FAKi and anti-PD1 antibody further depletes immunosuppressive cells in the TME including G-MDSCs, inflammatory resident monocytes and PDL1 expressing myeloid cells and appears to target the CXCR4 pathway through PEGPH20. These findings support testing the combination of FAKi and anti-PD1 antibody with agents targeting CXCR4 directly or indirectly by PEGPH20 in human PDAC.Disclosure InformationA. Osipov: None. L. Zheng: None.

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Natarajan, Vikneshwari, Alexander Delgado, Reed Jacobson, Lina Alhalhooly, Yongki Choi, Sangdeuk Ha, and Jiha Kim. "Abstract LB053: PDAC derived exosomes manipulate tumor pericyte phenotype." Cancer Research 82, no. 12_Supplement (June 15, 2022): LB053. http://dx.doi.org/10.1158/1538-7445.am2022-lb053.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in men and women in the U.S., with a 5-year survival rate of 10%. This poor prognosis is partly due to the aggressive nature of the disease, lack of early detection methods, its complex and dense tumor microenvironment (TME), and lack of effective treatment options. Within the PDAC TME, morphologically aberrant leaky vessels are responsible for hypoxia and impaired immune response, which likely reduces the efficacy of cancer therapies. We and others showed that pericyte coverage significantly correlates with vascular integrity/function and intratumoral hypoxia. Therefore, understanding perivascular heterogeneity and the unique contribution of each phenotype to the TME evolution is a critical step towards personalized treatment options for PDAC. Our study revealed that tumor-associated pericytes across all PDAC tumor tissues exhibited ectopic αSMA expression up to 10X higher compared to the normal pericytes. This aberrant pericyte phenotype was correlated with vascular leakiness and hypoxia, whereas the Des+ mature pericyte phenotype was inversely correlated with vessel leakiness. Our attempt to elucidate the underlying mechanism of pericyte phenotype switching using in vitro culture system shows that pancreatic cancer cell-derived extracellular vesicles (PC-Exo) is a potent inducer of αSMA expression in pericyte. PC-Exo was also sufficient enough to induce αSMA expression in normal pericytes within the pancreas when injected into the WT mice. In addition to the changes in pericyte markers, PC-Exo stimulated pericytes exhibited immunomodulatory phenotype with significantly higher expression of HLA-DRA, CD274, CD80, E-selectin, and P-selectin. Considering αSMA is a cytoskeletal protein that can influence cellular stiffness, migration, and downstream signaling, we also examined the biomechanical properties of pericytes with altered phenotype. The results show a significant increase in pericyte stiffness and cellular height of aSMA+ pericyte. These pericytes also have elongated morphology and cytoskeletal reorganization visualized by αSMA and phalloidin immunostaining. A recent study showed that acquired αSMA expression converts capillary pericytes into contractile vascular smooth muscle-like cells. Blood vessels are constricted and collapsed within the PDAC TME, which may be partly caused by an abundance of αSMA+ pericytes. In conclusion, our study indicates that tumor-associated pericytes undergo phenotype switching under the influence of pancreatic cancer cells, and these aberrant pericytes might contribute to non-optimal vascular integrity/function. Together, our study indicates that tumor conditioned αSMA+ pericytes present mechanical abnormalities and immune-suppressive features. Future work includes exploring the vascular normalization approach by suppressing pericyte phenotype switching to enhance vascular function and chemo- and immunotherapeutic efficacy. Citation Format: Vikneshwari Natarajan, Alexander Delgado, Reed Jacobson, Lina Alhalhooly, Yongki Choi, Sangdeuk Ha, Jiha Kim. PDAC derived exosomes manipulate tumor pericyte phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB053.

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Saab, Juan J. Apiz, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, and Alexander Muir. "Abstract B003: Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment." Cancer Research 82, no. 22_Supplement (November 15, 2022): B003. http://dx.doi.org/10.1158/1538-7445.panca22-b003.

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Abstract Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. We have used this information to develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. By transcriptomic analysis, we show that PDAC cells cultured in TIFM, compared to standard culture models, adopt a cellular state more similar to PDAC cells in tumors. Using the TIFM model, we then identified arginine biosynthesis as a critical metabolic adaptation PDAC cells engage to cope with microenvironmental nutrition. We further find that arginine biosynthesis enables PDAC cells to cope with microenvironmental arginine starvation, which we show is driven by myeloid cells in PDAC tumors. Altogether, these data show that nutrient availability in the microenvironment is an important determinant of PDAC metabolism and behavior, and models incorporating tumor nutrition enable detailed and mechanistic study of microenvironmentally-programmed PDAC cell states and phenotypes. Further, through use of the TIFM model, we identified both myeloid-driven arginine starvation as a major metabolic stress prevalent in the PDAC microenvironment, and the metabolic adaptations PDAC cells use to counter this nutritional challenge. Citation Format: Juan J. Apiz Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir. Pancreatic cancer cells activate arginine biosynthesis to adapt to myeloid-driven amino acid stress in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B003.

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Buscail, Etienne, Catherine Alix-Panabières, Pascaline Quincy, Thomas Cauvin, Alexandre Chauvet, Olivier Degrandi, Charline Caumont, et al. "High Clinical Value of Liquid Biopsy to Detect Circulating Tumor Cells and Tumor Exosomes in Pancreatic Ductal Adenocarcinoma Patients Eligible for Up-Front Surgery." Cancers 11, no. 11 (October 26, 2019): 1656. http://dx.doi.org/10.3390/cancers11111656.

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Purpose: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. Experimental design: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. Results: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. Conclusion: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

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Hollingsworth, Michael, Kamiya Mehla, Kirsten Eberle, Ying Huang, Aleata Triplett, Paul Grandgenett, Clara Mundry, and Thomas Caffrey. "654 Analysis of IDO-1 expression on dendritic cells and factors influencing its up- and downregulation in pancreatic cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A683. http://dx.doi.org/10.1136/jitc-2021-sitc2021.654.

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BackgroundPancreatic Ductal Adenocarcinoma (PDAC) is bad. An immunosuppressive tumor microenvironment (TME) with an excess of immunosuppressive immune cells and cytokine/chemokine factors contribute to local and systemic immunosuppression in PDAC.1 Our laboratory has generated single-cell RNA-Sequencing (scRNA-Seq.) data from spleens derived from PDAC patients and healthy counterparts. This data demonstrates the existence of dendritic cell (DC) subsets with a tolerogenic phenotype. These DCs display increased expression of several markers, including Indoleamine 2,3-dioxygenases (IDO-1 and IDO-2), widely accepted as markers for a specific population of DCs: tolerogenic DCs. These cells evoke an immunosuppressive signal leading to activation of regulatory T cells and MDSCs as well as apoptosis of CD8+ and CD4+ effector T cells.2 3MethodsTo validate our scRNA-Seq. data, we performed pilot investigations harvesting DCs from the spleen of PDAC patients and healthy subjects. Besides examining human specimens, we also investigated the IDO-1 expression on splenic DCs from tumor-bearing mice, orthotopically implanted with LSL-KrasG12D; LSL-Trp53R172H/+; Pdx1-Cre (KPC)-derived cell lines. It is known that tumor-derived exosomes can impact DC-differentiation to a tolerogenic phenotype.4 Exosome purification using differential ultracentrifugation is a well-established method in our lab and optimized for our autopsy samples. We analyzed tumor-derived exosomes for their potential in modulating IDO-1 expression on DCs in in vitro assays. Briefly, we incubated DCs with different exosome concentrations and harvested the cells for RNA-sequencing and flow cytometry.ResultsCompared to normal spleens, DCs from PDAC spleens displayed higher expression of IDO-1 (figure 1). Additionally, KPC-tumor-bearing mice showed higher expression of IDO-1 on DCs from the spleen and blood compared to wild-type mice. Further investigating the influence of PDAC-derived exosomes on marker expression on DCs have shown an apparent increase in expression of IDO-1 when culturing splenic-derived DCs with tumor-derived exosomes (figure 2).ConclusionsWhile tolerogenic DCs are essential in regulating the homeostasis between immune response and immune tolerance,5 several studies have shown IDO-1 overexpression in cancer. Investigating tolerogenic DCs is an essential part of our lab's efforts to understand the nature of the immune response in PDAC. Future directions for this project include determining molecular pathways that regulate the expression of IDO-1. Additionally, we will investigate downstream mechanisms through which exosomes modulate the switch to a tolerogenic phenotype. We also plan to further characterize different splenic DC populations by evaluating their interplay with other immune cells in the context of antigen-specificity and other factors influencing these cells' properties.ReferencesMundry CS, Eberle KC, Singh PK, Hollingsworth MA, Mehla K. Local and systemic immunosuppression in pancreatic cancer: targeting the stalwarts in tumor's arsenal. BBA - Reviews on Cancer 2020;1874(1):188387.Liu M, Wang X, Wang L, Ma X, Gong Z, Zhang S, Li Y. Targeting the IDO1 pathway in cancer: from bench to bedside. Journal of Hematology & Oncology 2018;11(1):100.Hornyák L, Dobos N, Koncz G, Karányi Z, Páll D, Szabó Z, Halmos G, Székvölgyi L. The role of Indoleamine-2,3-Dioxygenase in cancer development, diagnostics, and therapy. Frontiers in immunology 2018;9:1.Bronte V, Pittet MJ. The spleen in local and systemic regulation of immunity. Immunity 2013;39(5):806–818.Domogalla MP, Rostan PV, Raker VK, Steinbrink K. Tolerance through education: how tolerogenic dendritic cells shape immunity. Frontiers in Immunology 2017;8:1764.Ethics ApprovalThis study was approved by the University of Nebraska Medical Center Ethics Board; approval numbers IRB#: 440-16-EP and IRB#: 091-01.Abstract 654 Figure 1Expression of IDO-1 and IDO-2 on DCs from PDAC spleen (blue) .and normal spleen (orange)Abstract 654 Figure 2Change in expression of IDO-1 through treatment of DCs with different concentrations of tumor-derived exosomes

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Arnoletti, Juan Pablo, Joseph Reza, Armando Rosales, Alberto Monreal, Na’im Fanaian, Suzanne Whisner, Milan Srivastava, et al. "Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation." PLOS ONE 17, no. 3 (March 22, 2022): e0265725. http://dx.doi.org/10.1371/journal.pone.0265725.

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The portal venous circulation provides a conduit for pancreatic ductal adenocarcinoma (PDAC) tumor cells to the liver parenchyma sinusoids, a frequent site of metastasis. Turbulent flow in the portal circulation promotes retention of PDAC shed circulating tumor cells (CTC) and myeloid-derived immunosuppressor cells (MDSC). Excessive colony stimulating factor-1 receptor (CSF1R) signaling can induce myeloid differentiation to MDSC and transformation of MDSC to myeloid-derived fibroblasts (M-FB). Interactions between PDAC CTC and M-FB in the portal blood promotes the formation of immunoresistant clusters that enhance CTC proliferation, migration, and survival. Analysis of portal and peripheral blood samples collected intraoperatively from 30 PDAC patients undergoing pancreatico-duodenectomy showed that PDAC patient plasma contained high levels of macrophage colony stimulating factor (M-CSF/CSF1), granulocyte-macrophage colony stimulating factor (GM-CSF/CSF2), interleukin-8 (IL-8), and interleukin-34 (IL-34) compared to healthy control levels. Moreover, the level of M-CSF in portal blood was significantly higher than that detected in the peripheral blood of PDAC patients. PDAC CTC aseptically isolated by fluorescence activated cell sorting (FACS) out of freshly collected patient portal blood mononuclear cells (PortalBMC) had elevated RNA expression of IL34 (IL-34 gene) and CSF1 (M-CSF/CSF1 gene) which both signal through CSF1R. PDAC CTC also had high levels of RNA expression for CXCL8, the gene encoding chemokine interleukin-8 (IL-8) which can attract myeloid cells through their CXCR2 receptors. FACS-isolated portal PDAC CTC and M-FB co-cultured ex vivo had increased CTC proliferation, motility, and cluster formation compared to CTC cultured alone. CSF1R and CXCR2 cell surface expression were found on PDAC portal blood CTC and M-FB, suggesting that both cell types may respond to M-CSF, IL-34, and IL-8-mediated signaling. Portal PDAC CTC displayed enhanced RNA expression of CSF1 and IL34, while CTC+M-FB+ clusters formed in vivo had increased RNA expression of CSF2 and IL34. Portal M-FB were found to have high CSF1R RNA expression. CTC isolated from ex vivo 7-day cultures of PDAC patient portal blood mononuclear cells (PortalBMC) expressed elevated CSF1, IL34, and IL8 RNA, and CSF1 expression was elevated in M-FB. Treatment with rabbit anti-CSF1R antibodies decreased CTC proliferation. Treatment of PortalBMC cultures with humanized anti-CSF1R, humanized anti-IL-8, or anti-IL-34 antibodies disrupted CTC cluster formation and increased CTC apoptosis. U937 myeloid precursor cell line cultures treated with conditioned media from PortalBMC ex vivo cultures without treatment or treated with anti-IL-8 and/or anti-CSF1R did not prevent myeloid differentiation in the myeloid precursor cell line U937 to macrophage, dendritic cell, MDSC, and M-FB phenotypes; whereas, U937 cultures treated with conditioned media from PortalBMC ex vivo cultures exposed to anti-IL-34 were significantly inhibited in their myeloid differentiation to all but the M-FB phenotype. PDAC patient T cells that were found phenotypically anergic (CD3+CD25+CTLA4+PD1L1+) in PortalBMC could be re-activated (CD3+CD25+CTLA4-PD1L1-), and displayed increased interferon gamma (IFNγ) production when PortalBMC ex vivo cultures were treated with anti-CSF1R, anti-IL-8, and anti-IL-34 antibodies alone or in combination. These findings suggest that PDAC CTC have the potential to influence myeloid differentiation and/or antigen presenting cell activation in the PDAC portal blood microenvironment, and that disruption of CTC/M-FB interactions may be potential targets for reversing the immunosuppression supporting CTC survival in the portal blood.

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Xiang, Xiaoyu, Anton Poliakov, Cunren Liu, Yuelong Liu, Zhong-bin Deng, Jianhua Wang, Ziqiang Cheng, et al. "Induction of myeloid-derived suppressor cells by tumor exosomes." International Journal of Cancer 124, no. 11 (December 23, 2008): 2621–33. http://dx.doi.org/10.1002/ijc.24249.

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Flammang, Isabelle, Moritz Reese, Zixuan Yang, Johannes A. Eble, and Sameer A. Dhayat. "Tumor-Suppressive miR-192-5p Has Prognostic Value in Pancreatic Ductal Adenocarcinoma." Cancers 12, no. 6 (June 25, 2020): 1693. http://dx.doi.org/10.3390/cancers12061693.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by fast tumor progression and diagnosis at advanced, inoperable stages. Previous studies could demonstrate an involvement of miR-192-5p in epigenetic regulation of visceral carcinomas. Due to contradictory results, however, the clinical utility of miR-192-5p in PDAC has yet to be determined. MiR-192-5p expression was analyzed by RT-qRT-PCR in human PDAC and benign tissue (n = 78), blood serum (n = 81) and serum exosomes (n = 74), as well as in PDAC cell lines (n = 5), chemoresistant cell clones (n = 2), and pancreatic duct cell line H6c7. Analysis of EMT-associated (epithelial-to-mesenchymal transition) proteins was performed by immunohistochemistry and Western blot. MiR-192-5p was deregulated in PDAC as compared to healthy controls (HCs), with downregulation in macrodissected tissue (p < 0.001) and upregulation in blood serum of PDAC UICC (Union for International Cancer Control) stage IV (p = 0.016) and serum exosomes of PDAC UICC stages II to IV (p < 0.001). MiR-192-5p expression in tumor tissue was significantly lower as compared to corresponding peritumoral tissue (PDAC UICC stage II: p < 0.001; PDAC UICC stage III: p = 0.024), while EMT markers ZEB1 and ZEB2 were more frequently expressed in tumor tissue as compared to peritumoral tissue, HCs, and chronic pancreatitis. Tissue-derived (AUC of 0.86; p < 0.0001) and exosomal (AUC of 0.83; p = 0.0004) miR-192-5p could differentiate between PDAC and HCs with good accuracy. Furthermore, high expression of miR-192-5p in PDAC tissue of curatively resected PDAC patients correlated with prolonged overall and recurrence-free survival in multivariate analysis. In vitro, miR-192-5p was downregulated in gemcitabine-resistant cell clones of AsPC-1 (p = 0.029). Transient transfection of MIA PaCa-2 cells with miR-192-5p mimic resulted in downregulation of ZEB2. MiR-192-5p seems to possess a tumor-suppressive role and high potential as a diagnostic and prognostic marker in PDAC.

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Truong, Nhat Chau, Thao Nhi Huynh, Khuong Duy Pham, and Phuc Van Pham. "The role of tumor-derived exosomes in tumor immune escape: A concise review." Biomedical Research and Therapy 7, no. 11 (November 29, 2020): 4132–37. http://dx.doi.org/10.15419/bmrat.v7i11.650.

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Exosomes are small vesicles secreted by viable cells into the microenvironment. These vesicles bring various compositions, including lipids, RNAs and proteins, which carry information from producer cells to target cells. Cancer cells also produce exosomes, termed as tumor-derived exosomes (TDEs), which play important roles in immune modulation, angiogenesis and metastasis of tumors. This review summarizes the roles of TDEs in tumor immune escape mechanisms. TDEs affect all kinds of tumor-associated immune cells, including natural killer (NK) cells, dendritic cells (DCs), T and B lymphocytes, and myeloid-derived suppressor cells (MDSCs). Generally, TDEs suppress the immune system to promote tumor immune escape, thereby significantly contributing to tumorigenesis and metastasis.

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Waldenmaier, Mareike, Tanja Seibold, Thomas Seufferlein, and Tim Eiseler. "Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication." Cancers 13, no. 19 (September 28, 2021): 4844. http://dx.doi.org/10.3390/cancers13194844.

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Even with all recent advances in cancer therapy, pancreatic cancer still has a dismal 5-year survival rate of less than 7%. The most prevalent tumor subtype is pancreatic ductal adenocarcinoma (PDAC). PDACs display an extensive crosstalk with their tumor microenvironment (TME), e.g., pancreatic stellate cells, but also immune cells to regulate tumor growth, immune evasion, and metastasis. In addition to crosstalk in the local TME, PDACs were shown to induce the formation of pre-metastatic niches in different organs. Recent advances have attributed many of these interactions to intercellular communication by small extracellular vesicles (sEVs, exosomes). These nanovesicles are derived of endo-lysosomal structures (multivesicular bodies) with a size range of 30–150 nm. sEVs carry various bioactive cargos, such as proteins, lipids, DNA, mRNA, or miRNAs and act in an autocrine or paracrine fashion to educate recipient cells. In addition to tumor formation, progression, and metastasis, sEVs were described as potent biomarker platforms for diagnosis and prognosis of PDAC. Advances in sEV engineering have further indicated that sEVs might once be used as effective drug carriers. Thus, extensive sEV-based communication and applications as platform for biomarker analysis or vehicles for treatment suggest a major impact of sEVs in future PDAC research.

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Liu, Yuelong, Xiaoyu Xiang, Xiaoying Zhuang, Shuangyin Zhang, Cunren Liu, Ziqiang Cheng, Sue Michalek, William Grizzle, and Huang-Ge Zhang. "Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells (MDSC) (95.16)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 95.16. http://dx.doi.org/10.4049/jimmunol.184.supp.95.16.

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Abstract Tumor cells released membrane microvesicles - exosomes, can stimulate inflammation through MDSC, and then promote tumor growth by activating immunosuppressive networks. MyD88 is a cytoplasmic adaptor molecule essential for inducing inflammation via the TLR receptors. Very little is known about whether tumor exosome-mediated induction MDSCs and tumor growth is regulated through MyD88. In this study, we observed that mice pretreated with tumor exosomes had a significant acceleration of tumor metastasis in the lung. Tumor metastasis correlated significantly with an increase in recruitment of more MDSCs in the lung of B6 mice pretreated with tumor exosomes. These effects were blunted when MyD88 KO mice were pretreated with tumor exosomes. MDSCs induced by tumor exosomes and isolated from WT B6 mice are also more potent in inhibition of T cell activation and induction of IL-6 and TNF-α than MDSCs isolated from the lung of MyD88 KO mice via activation of the Stat3 pathway. Our in vitro data further support that addition of tumor exosomes to bone marrow derived CD11b+Gr-1+ cells isolated from WT B6 mice results in producing more cytokines, including TNF-α, IL-6 and the chemokine CCL2, than CD11b+Gr-1+ cells isolated from MyD88 KO mice. Less CCL2 in lung was observed in MyD88 KO mice pretreated with tumor exosomes than that in WT mice. Together these data demonstrate a pivotal role for MyD88 in tumor exosome-mediated induction of IL-6, TNF-α, expansion of MDSCs and tumor metastasis.

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Martinez, Marion, Marta Hergueta, Pilar Ximénez de Embún, Ana Dueso, David Torrents, Teresa Macarulla, Javier Muñoz, Héctor Peinado, and María Abad. "Abstract C074: Mining the secreted microproteome for novel regulators of PDAC progression." Cancer Research 82, no. 22_Supplement (November 15, 2022): C074. http://dx.doi.org/10.1158/1538-7445.panca22-c074.

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Abstract Recent work has unveiled a hidden microproteome composed by thousands of small proteins named microproteins: they are functional short proteins coded by genomic regions previously considered non-coding, and which had been completely ignored, mainly due to their small size (<100 aminoacids). To date, only a small part of the thousands of microproteins present in our cells have been characterized, and they are key players in fundamental processes such as DNA repair, mRNA splicing or cell metabolism. In cancer, they have been shown to regulate most tumor hallmarks, and present a huge potential for the clinic as diagnostic and prognostic biomarkers as well as therapeutic targets. Interestingly, their small size makes them ideal candidates to be shed in tumor-derived exosomes. PDAC-shed exosomes have been shown to prepare the pre-metastatic niche in the liver, and their presence in the bloodstream can be used as a surrogate marker of metastasis. Herein, we have mined the PDAC exosome-secreted microproteome for novel regulators of tumor progression and metastasis. Using proteogenomics in PDAC patient-derived explants, we have identified 439 microproteins secreted in exosomes by pancreatic tumors. We have selected a set of top microprotein candidates for further characterization by in silico analyses (e.g. phylogenetic conservation, predicted protein stability and localisation, mRNA expression in PDAC, etc). We have confirmed their exosome secretion in PDAC cell lines, and preliminary characterisation of these top candidates has shown that they extrinsically promote PDAC cell growth and invasion in vitro. Together, this work advances our knowledge on the underexplored field of secreted microproteins and provides pioneering evidence of their role in tumor cell communication in PDAC. It may further be a source of novel therapeutic targets and PDAC biomarkers for liquid biopsy in the clinic. Citation Format: Marion Martinez, Marta Hergueta, Pilar Ximénez de Embún, Ana Dueso, David Torrents, Teresa Macarulla, Javier Muñoz, Héctor Peinado, María Abad. Mining the secreted microproteome for novel regulators of PDAC progression [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C074.

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Choueiry, Fouad, Molly Torok, Reena Shakya, Kriti Agrawal, Anna Deems, Brooke Benner, Alice Hinton, et al. "CD200 promotes immunosuppression in the pancreatic tumor microenvironment." Journal for ImmunoTherapy of Cancer 8, no. 1 (June 2020): e000189. http://dx.doi.org/10.1136/jitc-2019-000189.

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BackgroundA significant challenge to overcome in pancreatic ductal adenocarcinoma (PDAC) is the profound systemic immunosuppression that renders this disease non-responsive to immunotherapy. Our supporting data provide evidence that CD200, a regulator of myeloid cell activity, is expressed in the PDAC microenvironment. Additionally, myeloid-derived suppressor cells (MDSC) isolated from patients with PDAC express elevated levels of the CD200 receptor (CD200R). Thus, we hypothesize that CD200 expression in the PDAC microenvironment limits responses to immunotherapy by promoting expansion and activity of MDSC.MethodsImmunofluorescent staining was used to determine expression of CD200 in murine and human PDAC tissue. Flow cytometry was utilized to test for CD200R expression by immune populations in patient blood samples. In vivo antibody blocking of CD200 was conducted in subcutaneous MT-5 tumor-bearing mice and in a genetically engineered PDAC model (KPC-Brca2 mice). Peripheral blood mononuclear cells (PBMC) from patients with PDAC were analyzed by single-cell RNA sequencing. MDSC expansion assays were completed using healthy donor PBMC stimulated with IL-6/GM-CSF in the presence of recombinant CD200 protein.ResultsWe found expression of CD200 by human pancreatic cell lines (BxPC3, MiaPaca2, and PANC-1) as well as on primary epithelial pancreatic tumor cells and smooth muscle actin+ stromal cells. CD200R expression was found to be elevated on CD11b+CD33+HLA-DRlo/− MDSC immune populations from patients with PDAC (p=0.0106). Higher expression levels of CD200R were observed in CD15+ MDSC compared with CD14+ MDSC (p<0.001). In vivo studies demonstrated that CD200 antibody blockade limited tumor progression in MT-5 subcutaneous tumor-bearing and in KPC-Brca2 mice (p<0.05). The percentage of intratumoral MDSC was significantly reduced in anti-CD200 treated mice compared with controls. Additionally, in vivo blockade of CD200 can also significantly enhance the efficacy of PD-1 checkpoint antibodies compared with single antibody therapies (p<0.05). Single-cell RNA sequencing of PBMC from patients revealed that CD200R+ MDSC expressed genes involved in cytokine signaling and MDSC expansion. Further, in vitro cytokine-driven expansion and the suppressive activity of human MDSC was enhanced when cocultured with recombinant CD200 protein.ConclusionsThese results indicate that CD200 expression in the PDAC microenvironment may regulate MDSC expansion and that targeting CD200 may enhance activity of checkpoint immunotherapy.

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Ivleva, Elena, Natalia Andreeva та Sergei Grivennikov. "Abstract 2117: IFN-γ signaling in myeloid cells regulates pancreatic cancer growth and progression". Cancer Research 82, № 12_Supplement (15 червня 2022): 2117. http://dx.doi.org/10.1158/1538-7445.am2022-2117.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by low survival, early metastasis, and rapidly emerging resistance to therapy. Interferon gamma (IFN-γ) signaling pathway is one of the key regulators of the tumor microenvironment in numerous cancer settings and its possible key role in myeloid cells is suggested. Here we investigated the IFN-y signaling in myeloid cells during PDAC development, progression, and metastasis using mice with conditional ablation of IFNgR2 in myeloid cells (IFNgR2-Delta-Mye). We performed an orthotopical injection of cells derived from conditional murine pancreatic model (Pdx1Cre-Kras-P53, or “KPC” cells) into IFNgR2-LysMCre (IFNgR2-Delta-Mye) mice. Ablation of IFN-γ signaling in myeloid cells led to a higher tumor burden compared to controls. Subsequent RNA sequence analysis demonstrated that IFN-γR2 deficiency in myeloid cells resulted in increased TGFβ1 gene expression as well as changes in metabolic and growth factor pathways in macrophages isolated from tumor tissue. Immunofluorescent analysis demonstrated that IFN-γR2 deletion in myeloid cells led to changes in cancer cell differentiation, resulting in a loss of characteristic epithelial histological pattern and shifting it towards more aggressive phenotype, possible via TGFβ1 dependent mechanism. Using murine model of liver metastasis, we found that loss of IFN-γR2 in myeloid cells leads to increased metastatic outgrowth of PDAC KPC cells. This effect was partially dependent on the gut microbiota, as shown by “separated and co-housed mice” experiments. Deficiency of IFN-γR2 in myeloid cells resulted in increased recruitment and infiltration of monocytes in normal and tumor/metastatic liver tissues. Our data identifies myeloid cell type specific IFN-γ signaling pathway as an important regulator of pancreatic cancer progression and metastasis, that can be potentially exploited as a novel immunooncology target. Citation Format: Elena Ivleva, Natalia Andreeva, Sergei Grivennikov. IFN-γ signaling in myeloid cells regulates pancreatic cancer growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2117.

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Surana, Rishi, Valerie S. LeBleu, J. Jack Lee, Brandon George Smaglo, Dan Zhao, Michael Sangmin Lee, Robert A. Wolff, et al. "Phase I study of mesenchymal stem cell (MSC)-derived exosomes with KRAS^G12DsiRNA in patients with metastatic pancreatic cancer harboring a KRAS^G12D mutation." Journal of Clinical Oncology 40, no. 4_suppl (February 1, 2022): TPS633. http://dx.doi.org/10.1200/jco.2022.40.4_suppl.tps633.

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TPS633 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with few effective therapeutic options. Over 90% of patients with PDAC harbor activating mutations in KRAS, a known oncogenic driver of tumor growth, cancer cell survival and metastasis thus making for an attractive therapeutic target. However, targeting the most common KRAS mutations in pancreatic cancer (KRASG12D and KRASG12V) remains a pharmacological challenge. Exosomes are extracellular nano-vesicles that are efficiently internalized by target cells and are under investigation as a drug-delivery vehicle for various therapeutic payloads, including nucleic acids such as small interfering RNA (siRNA). Previously published pre-clinical data demonstrate effective delivery of exosomes loaded with siRNA targeting KRASG12D leading to tumor control in various murine models of PDAC. Methods: This is a single arm, single institution, phase I trial evaluating treatment with KRASG12D-siRNA loaded exosomes. Large-scale production of KRASG12D-siRNA loaded exosomes from mesenchymal stromal cells will be performed at the MD Anderson Cancer Center using pre-specified GMP-compliant protocols. The primary endpoints of this study are to determine a maximum tolerated dose (MTD) of KRASG12D-loaded exosomes and to identify dose-limiting toxicities (DLT). Key secondary endpoints include the pharmacokinetics of circulating exosomes, overall response rate, disease control rate (defined as partial responses and patients with stable disease), median progression-free survival (PFS) and median overall survival (OS). Key inclusion criteria include histologically confirmed metastatic pancreatic ductal adenocarcinoma, documented progression on one or more lines of systemic therapy, and documented presence of a KRASG12D mutation. Selected correlative studies include measurement of circulating siRNA and KRASG12D DNA using PCR. This trial will enroll up to 28 patients and will follow a 3+3 design for dose escalation. This trial is actively accruing and has enrolled six patients at the time of submission. Clinical trial information: NCT03608631.

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Rubin, Samuel J. S., Raoul S. Sojwal, John Gubatan, and Stephan Rogalla. "The Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Neither Hot nor Cold." Cancers 14, no. 17 (August 31, 2022): 4236. http://dx.doi.org/10.3390/cancers14174236.

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Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor and is associated with poor prognosis and treatment response. The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. While earlier work characterized PDAC as an immunologically privileged tumor poorly recognized by the immune system, recent studies revealed the important and nuanced roles of immune cells in the pathogenesis of PDAC. Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical “hot” versus “cold” tumor distinction. We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field.

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Walsh, R. McKinnon, Joseph Ambrose, Bailey A. Bye, Austin E. Eades, Jarrid L. Jack, Mariana T. Ruckert, Appolinaire A. Olou, et al. "Abstract C060: Adipose-tumor crosstalk alters tumor immune profile by promoting PDAC CXCL5 secretion." Cancer Research 82, no. 22_Supplement (November 15, 2022): C060. http://dx.doi.org/10.1158/1538-7445.panca22-c060.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death in the US, due to late detection and limited therapeutic options. While the main cause of PDAC remains unknown, obesity has been shown to be a major risk factor. However, the molecular mechanisms behind adipose-tumor crosstalk are still being elucidated. Therefore, understanding the crosstalk between adipose and PDAC is critical for improving therapeutic approaches. We hypothesize that factors secreted by the adipose tissue reprogram pancreatic cancer cells to drive tumor growth and anti-tumor immunity. We observed enhanced proliferation in cells treated with conditioned media made from adipose tissue collected from PDAC [MV1] patients. Subsequent analysis determined that PDAC cells also secrete high levels of CXCL5 in response to stimulation with adipose conditioned media. Pathway analysis of RNA-sequencing data from conditioned-media-treated human PDAC cell lines implicated IL-1β and TNF-α as being involved in the resulting transcript changes. Using recombinant IL-1β, we stimulated CXCL5 secretion from multiple PDAC cell lines. Additionally, we found an enhanced secretion of IL-1β from obese adipose tissue compared to that from lean adipose and, using an anti-IL-1β blocking antibody we were able to partially depress the CXCL5 secretion from cells stimulated with adipose conditioned media. Because CXCL5 is a known neutrophil activating and attracting protein, we used CRISPR to engineer CXCL5 deficient murine PDAC cells. To determine the effect of tumor-derived CXCL5 on PDAC growth and immune recruitment, we orthotopically injected non-targeting-control and CXCL5-KO K8484 cells into wild-type, syngeneic, obese mice. While CXCL5-KO tumors displayed a similar size, we observed a significant change in the tumor immune profile. Despite an increase in the pro-tumorigenic monocytic myeloid derived suppressor cells (MDSCs), we found that the CXCL5-KO tumors exhibited a significantly enhanced CD8+ T cell infiltration. However, a high percentage of these CD8+ T cells were PD-1 positive, implicating an exhausted phenotype. Subsequently, we treated wildtype and CXCL5 deficient PDAC bearing obese mice with an anti-PD-1 antibody to promote T-cell re-activation, which resulted in a significantly reduced growth of the CXCL5 deficient tumors. In conclusion, obesity and adipose derived factors directly induce tumor cells to support immune suppression and drive PDAC progression. Citation Format: R. McKinnon Walsh, Joseph Ambrose, Bailey A. Bye, Austin E. Eades, Jarrid L. Jack, Mariana T. Ruckert, Appolinaire A. Olou, Fanuel Messaggio, Prabhakar Chalise, Dong Pei, Michael N. VanSaun. Adipose-tumor crosstalk alters tumor immune profile by promoting PDAC CXCL5 secretion [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C060.

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Liu, Jing, Wenna Jiang, Kaili Zhao, Hongwei Wang, Tianxing Zhou, Weiwei Bai, Xiuchao Wang, et al. "Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma." Journal of Experimental Medicine 216, no. 3 (February 7, 2019): 656–73. http://dx.doi.org/10.1084/jem.20180749.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly immune-suppressive tumor with a low response rate to single checkpoint blockade therapy. ETS homologous factor (EHF) is a tumor suppressor in PDAC. Here, we report a novel function of EHF in pancreatic cancer immune microenvironment editing and efficacy prediction for anti-PD1 therapy. Our findings support that the deficiency of tumoral EHF induced the accumulation of regulatory T (T reg) cells and myeloid-derived suppressor cells (MDSCs) and a decrease in the number of tumor-infiltrating CD8+ T cells. Mechanistically, EHF deficiency induced the conversion and expansion of T reg cells and MDSCs through inhibiting tumor TGFβ1 and GM-CSF secretion. EHF suppressed the transcription of TGFB1 and CSF2 by directly binding to their promoters. Mice bearing EHF overexpression tumors exhibited significantly better response to anti-PD1 therapy than those with control tumors. Our findings delineate the immunosuppressive mechanism of EHF deficiency in PDAC and highlight that EHF overexpression may improve PDAC checkpoint immunotherapy.

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Apiz-Saab, Juan, and Alex Muir. "Abstract 2177: Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2177. http://dx.doi.org/10.1158/1538-7445.am2022-2177.

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Abstract Arginine is an amino acid critical for various cellular processes, not only protein synthesis but also metabolism of other essential metabolites, like polyamines, as well as a signaling factor for pathways such as the growth regulator mTOR. Previously, our group measured arginine levels in the interstitial fluid of tumors (TIF) of pancreatic ductal adenocarcinoma (PDAC) murine models and found extremely low arginine levels (2-5 uM) in the tumor microenvironment (TME). Despite near complete absence of this critical nutrient in the TME, pancreatic tumors exhibit aggressive growth. We have sought to understand both how the PDAC TME becomes arginine limited and how PDAC cells adapt to proliferate in the absence of arginine. Using genetically engineered mice, we find that arginase activity in the myeloid compartment of PDAC tumors is responsible for arginine depletion in the TME. Staining of Arg1+ myeloid populations in human PDAC samples suggest a similar mechanism reduces arginine availability in human PDAC tumors as well. We then leveraged our newfound knowledge of PDAC TIF composition to develop a novel ex vivo cell culture media formulation with physiologically relevant nutrient levels and monitored arginine acquisition pathways using isotope tracing and metabolomics assays to determine how PDAC cells cope with arginine deprivation. Under TME nutrient conditions, PDAC cells consume available citrulline and use it to produce arginine by de novo synthesis. Starving cells of citrulline or genetically perturbing arginosuccinate synthase (ASS1), key enzyme in arginine biosynthesis, significantly reduces PDAC cellular arginine and proliferative capacity. Immunohistochemical analysis of both human and mouse PDAC tumors indicates that the de novo arginine synthesis pathway is highly expressed in PDAC but not in untransformed pancreas, suggesting a key role for this pathway in PDAC progression. Altogether, we find that myeloid-derived arginase challenges PDAC cells by limiting arginine availability and suggest that de novo arginine synthesis may be a critical metabolic pathway that enables PDAC tumors to cope with this metabolic challenge. Citation Format: Juan Apiz-Saab, Alex Muir. Myeloid-derived arginase depletes microenvironmental arginine in PDAC tumors and leads to activation of arginine de novo biosynthesis in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2177.

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Schwarzenbach, Heidi, and Peter B. Gahan. "Exosomes in Immune Regulation." Non-Coding RNA 7, no. 1 (January 8, 2021): 4. http://dx.doi.org/10.3390/ncrna7010004.

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Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of immune cells and immune escape of tumor cells supporting cancer progression and metastasis. Therefore, current investigations focus on the regulation of exosome levels for immunotherapeutic interventions. In this review, we discuss the role of exosomes in immunomodulation of lymphoid and myeloid cells, and their use as immune stimulatory agents to elicit specific cytotoxic responses against the tumor.

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Schwarzenbach, Heidi, and Peter B. Gahan. "Exosomes in Immune Regulation." Non-Coding RNA 7, no. 1 (January 8, 2021): 4. http://dx.doi.org/10.3390/ncrna7010004.

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Exosomes, small extracellular vesicles mediate intercellular communication by transferring their cargo including DNA, RNA, proteins and lipids from cell to cell. Notably, in the immune system, they have protective functions. However in cancer, exosomes acquire new, immunosuppressive properties that cause the dysregulation of immune cells and immune escape of tumor cells supporting cancer progression and metastasis. Therefore, current investigations focus on the regulation of exosome levels for immunotherapeutic interventions. In this review, we discuss the role of exosomes in immunomodulation of lymphoid and myeloid cells, and their use as immune stimulatory agents to elicit specific cytotoxic responses against the tumor.

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Chen, Wuzhen, Jingxin Jiang, Wenjie Xia, and Jian Huang. "Tumor-Related Exosomes Contribute to Tumor-Promoting Microenvironment: An Immunological Perspective." Journal of Immunology Research 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/1073947.

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Exosomes are a kind of cell-released membrane-form structures which contain proteins, lipids, and nucleic acids. These vesicular organelles play a key role in intercellular communication. Numerous experiments demonstrated that tumor-related exosomes (TEXs) can induce immune surveillance in the microenvironment in vivo and in vitro. They can interfere with the maturation of DC cells, impair NK cell activation, induce myeloid-derived suppressor cells, and educate macrophages into protumor phenotype. They can also selectively induce effector T cell apoptosis via Fas/FasL interaction and enhance regulatory T cell proliferation and function by releasing TGF-β. In this review, we focus on the TEX-induced immunosuppression and microenvironment change. Based on the truth that TEXs play crucial roles in suppressing the immune system, studies on modification of exosomes as immunotherapy strategies will also be discussed.

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De Sanctis, Francesco, Alessia Lamolinara, Federico Boschi, Chiara Musiu, Simone Caligola, Rosalinda Trovato, Alessandra Fiore, et al. "Interrupting the nitrosative stress fuels tumor-specific cytotoxic T lymphocytes in pancreatic cancer." Journal for ImmunoTherapy of Cancer 10, no. 1 (January 2022): e003549. http://dx.doi.org/10.1136/jitc-2021-003549.

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors owing to its robust desmoplasia, low immunogenicity, and recruitment of cancer-conditioned, immunoregulatory myeloid cells. These features strongly limit the success of immunotherapy as a single agent, thereby suggesting the need for the development of a multitargeted approach. The goal is to foster T lymphocyte infiltration within the tumor landscape and neutralize cancer-triggered immune suppression, to enhance the therapeutic effectiveness of immune-based treatments, such as anticancer adoptive cell therapy (ACT).MethodsWe examined the contribution of immunosuppressive myeloid cells expressing arginase 1 and nitric oxide synthase 2 in building up a reactive nitrogen species (RNS)-dependent chemical barrier and shaping the PDAC immune landscape. We examined the impact of pharmacological RNS interference on overcoming the recruitment and immunosuppressive activity of tumor-expanded myeloid cells, which render pancreatic cancers resistant to immunotherapy.ResultsPDAC progression is marked by a stepwise infiltration of myeloid cells, which enforces a highly immunosuppressive microenvironment through the uncontrolled metabolism of L-arginine by arginase 1 and inducible nitric oxide synthase activity, resulting in the production of large amounts of reactive oxygen and nitrogen species. The extensive accumulation of myeloid suppressing cells and nitrated tyrosines (nitrotyrosine, N-Ty) establishes an RNS-dependent chemical barrier that impairs tumor infiltration by T lymphocytes and restricts the efficacy of adoptive immunotherapy. A pharmacological treatment with AT38 ([3-(aminocarbonyl)furoxan-4-yl]methyl salicylate) reprograms the tumor microenvironment from protumoral to antitumoral, which supports T lymphocyte entrance within the tumor core and aids the efficacy of ACT with telomerase-specific cytotoxic T lymphocytes.ConclusionsTumor microenvironment reprogramming by ablating aberrant RNS production bypasses the current limits of immunotherapy in PDAC by overcoming immune resistance.

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Wang, Meng, and Bo Zhang. "The Immunomodulation Potential of Exosomes in Tumor Microenvironment." Journal of Immunology Research 2021 (September 27, 2021): 1–11. http://dx.doi.org/10.1155/2021/3710372.

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Exosomes are lipid bilayer particles that originated from almost all types of cells and play an important role in intercellular communication. Tumor-derived exosomes contain large amounts of noncoding RNA, DNA, and proteins, which can be transferred into recipient cells as functional components in exosomes. These exosomal functional constituents depend on the originating cells, and it has been proved that types and numbers of exosomal components differ in cancer patients and healthy individuals. This review summarizes the role of tumor-derived exosomes in immunomodulation and discusses the application of exosomes in immunotherapy in cancers. Overall, exosomes isolated from cancer cells are turned out to promote immune evasion and interfere with immune responses in tumors through inducing apoptosis of CD8+ T cells, facilitating generation of Tregs, suppressing natural killer (NK) cell cytotoxicity, inhibiting maturation and differentiation of monocyte, and enhancing suppressive function of myeloid-derived suppressor cells (MDSCs). Mechanistically, exosomal functional components play a significant role in the immunomodulation in cancers. Moreover, based on the existing studies, exosomes could potentially serve as therapeutic delivery vehicles, noninvasive biomarkers, and immunotherapeutic vaccines for various types of cancers.

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Byrne, Katelyn T., Samuel I. Kim, Charu Arora, Ioannis I. Verginadis, Christopher R. Cassella, Nune Markosyan, Constantinos Koumenis, and Robert H. Vonderheide. "CD4+ T cells mediate non-canonical rejection of major histocompatibility class-I deficient pancreatic tumors independently of CD8+ T cells." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 180.07. http://dx.doi.org/10.4049/jimmunol.208.supp.180.07.

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Abstract Cytolytic CD8+ T cells are a major mediator of immune-induced tumor rejection, but many patients have primary or acquired resistance to CD8+ T cell immunity. Reduced major histocompatibility complex I (MHC I) expression contributes to resistance, including treatment-refractory pancreatic ductal adenocarcinoma (PDAC). Interrogating interventions in PDAC will reveal novel mechanisms regulating sensitivity to immunotherapy. Using a genetically engineered mouse model of PDAC, we previously reported that agonistic anti-CD40 and dual immune checkpoint blockade (ICB) induces CD8+ and a CD4+ T cell responses mediating tumor rejection. Here, we utilized CRISPR− Cas9 to disrupt the dominant MHC I (H-2Kb) allele expression in PDAC cell lines, precluding direct antigen presentation to CD8+ T cells. Injection of MHC I-deficient tumor clones revealed normal tumor growth at baseline, and significantly delayed tumor growth in response to CD40/ICB in a CD4+ T cell-dependent manner (p < 0.0001 vs. vehicle-treated mice). There was no direct contribution of tumor rejection by CD8+ T cells, despite the generation of a tumor-specific response (24.5% vs. 1.98% in vehicle-treated mice, p<0.003). CD4+ T cells upregulated IFN-γ production (52.3% vs. 11.9% in vehicle-treated mice, p<0.0001), and host IFN-γ expression was required. No changes were observed in the expression of cytotoxic molecules by CD4+ T cells after CD40/ICB, and depletion of myeloid cells did not dampen treatment efficacy. Thus, CD4+ T cells mediated PDAC rejection via non-canonical mechanisms after treatment with CD40/ICB. This study provides critical insight into novel mediators of tumor clearance, and opportunities to exploit CD4 T+ cells as regulators of tumor immunity. Funded by the Parker Institute for Cancer Immunotherapy.

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Christopher, Ben N., Reeder Robinson, Leticia Reyes, Lena Golick, Ashton Basar, and Nathan Dolloff. "Abstract C035: Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma." Cancer Research 82, no. 22_Supplement (November 15, 2022): C035. http://dx.doi.org/10.1158/1538-7445.panca22-c035.

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Abstract Pancreatic Ductal Adenocarcinoma (PDAC) has a 5-year survival rate of only 10%, and limited treatment options exist. Immune checkpoint inhibitors are effective in a variety of cancer types; however, the complex immunosuppressive tumor microenvironment (TME) of PDAC is a significant barrier to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are abundant in PDAC tumors from humans and mouse models. MDSCs suppress effector T cell function, leading us to hypothesize that targeting tumor MDSCs would be an effective therapeutic strategy for PDAC and enhance the efficacy of T cell-based immunotherapy. Our preliminary data and the work from others shows that CXCR2 ligands such as CXCL8/IL-8, CXCL5/ENA78, and CXCL1/GROα are the most abundant soluble factors secreted by PDAC cells. CXCR2 ligands are critical for the homing of myeloid cells to sites of injury in cutaneous wound healing, suggesting that dysregulated secretion of CXCR2 chemokines in PDAC may mimic a wound healing response that attracts myeloid cells and promotes the expansion of MDSCs and an immunosuppressive TME. To test this hypothesis, we have designed multiple biotherapeutic molecules that exploit CXCL5/ENA78 and CXCL1/GROa to target and eliminate MDSCs from PDAC tumors. Specifically, we have generated Pseudomonas aeruginosa exotoxin (ExoA) and IgG-Fc fusion proteins that will be used to deliver cytotoxic payloads to MDSCs. A variety of CXCR2 knockout and knock-in models will be used to demonstrate CXCR2 dependence and elimination of MDSCs in vitro. In vivo, we are utilizing the KPC (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre) mouse model of PDAC, which we've shown in preliminary studies to, like human PDAC, support an abundance of MDSCs in tumors as well as secondary lymphoid organs such as the spleen. We anticipate that this study will demonstrate the therapeutic potential and actionability of targeting MDSCs and will provide novel biotherapeutic drug candidates that will ultimately improve immunotherapy outcomes in patients with PDAC. Citation Format: Ben N. Christopher, Reeder Robinson, Leticia Reyes, Lena Golick, Ashton Basar, Nathan Dolloff. Biotherapeutic strategies targeting the CXCR2 axis for depletion of myeloid-derived suppressor cells in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C035.

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Shimazaki, Reiri, Shigetsugu Takano, Mamoru Satoh, Mamoru Takada, Yoji Miyahara, Kosuke Sasaki, Hideyuki Yoshitomi, et al. "Complement factor B regulates cellular senescence and is associated with poor prognosis in pancreatic cancer." Cellular Oncology 44, no. 4 (June 1, 2021): 937–50. http://dx.doi.org/10.1007/s13402-021-00614-z.

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Abstract Background The interplay between cancer cells and stromal components, including soluble mediators released from cancer cells, contributes to the progression of pancreatic ductal adenocarcinoma (PDAC). Here, we set out to identify key secreted proteins involved in PDAC progression. Methods We performed secretome analyses of culture media of mouse pancreatic intraepithelial neoplasia (PanIN) and PDAC cells using Stable Isotope Labeling by Amino acid in Cell culture (SILAC) with click chemistry and liquid chromatography-mass spectrometry (LC-MS/MS). The results obtained were verified in primary PDAC tissue samples and cell line models. Results Complement factor B (CFB) was identified as one of the robustly upregulated proteins, and found to exhibit elevated expression in PDAC cells compared to PanIN cells. Endogenous CFB knockdown by a specific siRNA dramatically decreased the proliferation of PDAC cells, PANC-1 and MIA PaCa-II. CFB knockdown induced increases in the number of senescence-associated-β-galactosidase (SA-β-gal) positive cells exhibiting p21 expression upregulation, which promotes cellular senescence with cyclinD1 accumulation. Furthermore, CFB knockdown facilitated downregulation of proliferating cell nuclear antigen and led to cell cycle arrest in the G1 phase in PDAC cells. Using immunohistochemistry, we found that high stromal CFB expression was associated with unfavorable clinical outcomes with hematogenous dissemination after surgery in human PDAC patients. Despite the presence of enriched CD8+ tumor infiltrating lymphocytes in the PDAC tumor microenvironments, patients with a high stromal CFB expression exhibited a significantly poorer prognosis compared to those with a low stromal CFB expression. Immunofluorescence staining revealed a correlation between stromal CFB expression in the tumor microenvironment and an enrichment of immunosuppressive regulatory T-cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We also found that high stromal CFB expression showed a positive correlation with high CD8+/Foxp3+ Tregs populations in PDAC tissues. Conclusions Our data indicate that CFB, a key secreted protein, promotes proliferation by preventing cellular senescence and is associated with immunological tumor promotion in PDAC. These findings suggest that CFB may be a potential target for the treatment of PDAC.

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Pritchard, Alexandra, Sultan Tousif, Yong Wang, Kenneth Hough, Saad Khan, John Strenkowski, Balu K. Chacko, Victor M. Darley-Usmar, and Jessy S. Deshane. "Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization." Cells 9, no. 5 (May 24, 2020): 1303. http://dx.doi.org/10.3390/cells9051303.

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Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer.

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Chua, Kee Voon, Chi-Shuan Fan, Chia-Chi Chen, Li-Li Chen, Shu-Chen Hsieh та Tze-Sing Huang. "Octyl Gallate Induces Pancreatic Ductal Adenocarcinoma Cell Apoptosis and Suppresses Endothelial-Mesenchymal Transition-Promoted M2-Macrophages, HSP90α Secretion, and Tumor Growth". Cells 9, № 1 (30 грудня 2019): 91. http://dx.doi.org/10.3390/cells9010091.

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Octyl gallate (OG) is a common antioxidant and preservative safely used in food additive and cosmetics. In this study, OG exhibited an activity to induce apoptosis in pancreatic ductal adenocarcinoma (PDAC) cells. It induced BNIP3L level and facilitated physical associations of BNIP3L with Bcl-2 as well as Bcl-XL to set the mitochondrial Bax/Bak channels free for cytochrome c release. In addition, in vivo evaluation also showed that daily oral administration of OG was efficacious to prevent the tumor growth of PDAC cell grafts. Considering PDAC is a desmoplastic tumor consisting of many cancer-associated fibroblasts (CAFs), we further evaluated the efficacy of OG in a CAFs-involved PDAC mouse model. Endothelial-to-mesenchymal transition (EndoMT) is an important source of CAFs. The mix of EndoMT-derived CAFs with PDAC cell grafts significantly recruited myeloid-derived macrophages but prevented immune T cells. HSP90α secreted by EndoMT-derived CAFs further induced macrophage M2-polarization and more HSP90α secretion to expedite PDAC tumor growth. OG exhibited its potent efficacy against the tumor growth, M2-macrophages, and serum HSP90α level in the EndoMT-involved PDAC mouse model. CD91 and TLR4 are cell-surface receptors for extracellular HSP90α (eHSP90α). OG blocked eHSP90α–TLR4 ligation and, thus, prevented eHSP90α-induced M2-macrophages and more HSP90α secretion from macrophages and PDAC cells.

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Kim, Hong S., Jing Yang, Shuang Lu, Marina Pasca di Magliano, Kai Ge, and Jiaqi Shi. "Abstract C037: KMT2D loss in pancreatic cancer cells leads to an immunosuppressive tumor microenvironment by upregulating the interferon and inflammatory response pathways." Cancer Research 82, no. 22_Supplement (November 15, 2022): C037. http://dx.doi.org/10.1158/1538-7445.panca22-c037.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemoradiation and immune therapies, which is at least in part driven by its immunosuppressive tumor microenvironment (TME) consisting of dense cancer-associated fibroblasts (CAF) and highly suppressed immune cells. Lysine methyltransferase 2D (KMT2D), also known as MLL4 in mice, has been identified as one of the most frequently altered epigenetic regulators in PDAC. Most importantly, KMT2D mutation was found in more than 80% of neoadjuvant-treated PDAC, suggesting that KMT2D loss may be associated with treatment resistance. In human PDAC, low KMT2D protein level is correlated with worse survival. However, it is unknown whether KMT2D loss in PDAC cells modulates the TME. This project aimed to elucidate the role of KMT2D in remodeling the immune and stromal environment in PDAC. We first screened for changes in the immune cell population by performing immunohistochemistry (IHC) stains with human PDAC samples. We found that primary human tumors with low KMT2D expression had increased immunosuppressive tumor-associated neutrophils. xCell digital dissection analysis with The Cancer Genome Atlas (TCGA) data revealed that KMT2D-low PDAC had decreased effector T cell signature and enriched immunosuppressive Treg cell signature. Single-cell RNA sequencing analysis showed that KMT2D-low PDAC had increased suppressive myeloid cells and decreased CD8 T cells. We then generated Ptf1a-Cre; LSL-KrasG12D; Mll4+/+ (KCM+/+) and Ptf1a-Cre; LSL-KrasG12D; Mll4f/f (KCMf/f) mice to model pancreas-specific loss of Mll4 in the background of Kras mutation, a classic PDAC genetic mouse model. All KCM+/+ mice younger than 12 weeks had normal pancreas or low-grade pancreatic intraepithelial neoplasia (PanIN). In contrast, 66% of KCMf/f mice developed high-grade PanIN lesions or PDAC by 12 weeks. Immunohistochemistry staining showed that infiltration of immunosuppressive myeloid cells (tumor-associated macrophages and neutrophils) increased, whereas the presence of CD8+ T cells decreased in Mll4-deficient pancreata. Additionally, myofibroblastic CAFs, defined as PDPN+aSMA+ CAFs, decreased in KCMf/f mice pancreata compared to KCM+/+ pancreata. Mechanistically, we found that KMT2D loss in PDAC cells upregulates the interferon and inflammatory response pathways, including many cytokines and chemokines. These results suggest that KMT2D is a critical tumor suppressor, partly by promoting an immunogenic and tumor-suppressive TME. Cytokines in the interferon and inflammatory response pathways may serve as potential therapeutic targets, especially for treatment-resistant PDACs and KMT2D-deficient PDACs. Citation Format: Hong S. Kim, Jing Yang, Shuang Lu, Marina Pasca di Magliano, Kai Ge, Jiaqi Shi. KMT2D loss in pancreatic cancer cells leads to an immunosuppressive tumor microenvironment by upregulating the interferon and inflammatory response pathways [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C037.

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Tjomsland, Vegard, Lina Niklasson, Per Sandström, Kurt Borch, Henrik Druid, Charlotte Bratthäll, Davorka Messmer, Marie Larsson, and Anna Spångeus. "The Desmoplastic Stroma Plays an Essential Role in the Accumulation and Modulation of Infiltrated Immune Cells in Pancreatic Adenocarcinoma." Clinical and Developmental Immunology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/212810.

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Tumor microenvironment is composed of tumor cells, fibroblasts, and infiltrating immune cells, which all work together and create an inflammatory environment favoring tumor progression. The present study aimed to investigate the role of the desmoplastic stroma in pancreatic ductal adenocarcinoma (PDAC) regarding expression of inflammatory factors and infiltration of immune cells and their impact on the clinical outcome. The PDAC tissues examined expressed significantly increased levels of immunomodulatory and chemotactic factors (IL-6, TGFβ, IDO, COX-2, CCL2, and CCL20) and immune cell-specific markers corresponding to macrophages, myeloid, and plasmacytoid dendritic cells (DCs) as compared to controls. Furthermore, short-time survivors had the lowest levels of DC markers. Immunostainings indicated that the different immune cells and inflammatory factors are mainly localized to the desmoplastic stroma. Therapies modulating the inflammatory tumor microenvironment to promote the attraction of DCs and differentiation of monocytes into functional DCs might improve the survival of PDAC patients.

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Hansen, Nils, Pablo Peña, Finja Hansen, Petter Skoog, Susanne Larsson Faria, Karin von Wachenfeldt, Carl Högberg, Camilla Rydberg Millrud, David Liberg, and Marcus Järås. "Abstract C055: The IL1RAP-blocking antibody nadunolimab disrupts pancreatic cancer cell and fibroblast crosstalk, reduces recruitment of myeloid cells and inhibits tumor growth." Cancer Research 82, no. 22_Supplement (November 15, 2022): C055. http://dx.doi.org/10.1158/1538-7445.panca22-c055.

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Abstract IL1RAP is expressed by tumor and stromal cells in pancreatic ductal adenocarcinoma (PDAC). Signaling by IL1 through the IL1R1/IL1RAP complex promotes cancer progression and contributes to the immune suppressive microenvironment in PDAC. The IL1RAP-blocking antibody nadunolimab blocks the signaling of both IL-1a and IL-1b and is currently evaluated in a phase I/IIa clinical study for PDAC (NCT03267316). Cancer-associated fibroblasts (CAFs) are a primary constituent of the PDAC stroma and has previously been shown to be regulated by IL-1. The aim of this study was to explore the functional consequences of nadunolimab treatment on the crosstalk between tumor cells and CAFs. Co-cultures of the PDAC cell line BxPC3 and pancreatic CAFs induced major changes in gene expression of both cell types as determined by RNA sequencing, indicating an extensive communication between the two cell types. Inclusion of nadunolimab to the co-cultures resulted in only 6 differentially expressed genes (padj<0.05) in the BxPC3 cells but 294 differentially expressed genes (padj<0.05) in CAFs compared to an isotype control antibody. Among the nadunolimab-downregulated genes were several cytokines, including CXCL1, CXCL2, CXCL3, CXCL6, IL8 and CCL2 (padj<0.05). Hence, we next measured cytokine concentrations in the co-culture medium and confirmed that nadunolimab treatment resulted in significant reductions of CXCL1, LIF, IL8 and CSF3 (p<0.05). We also found reduced levels of CCL2 (p=0.059). To identify which biological processes were affected by nadunolimab, we performed gene set enrichment analysis (GSEA). Nadunolimab induced a gene expression signature in the CAFs with negative enrichments of mononuclear cell migration (padj 0.003) and monocyte chemotaxis (padj 0.003). In line with these findings, conditioned media from co-cultures treated with nadunolimab exhibited reduced capacity to stimulate migration of peripheral blood monocytes in transwell assays (p=0.033). Interestingly, blockade of IL1b only using a neutralizing anti-IL1b antibody did not affect cell migration, suggesting that the broader blockage of cytokine signaling by nadunolimab was required to reduce monocyte migration. To assess whether the effects of IL1RAP-blockade by nadunolimab on PDAC-CAF crosstalk is relevant for tumor growth in vivo, PDAC cells and fibroblasts or PDAC cells alone were subcutaneously inoculated in Balb/c nude mice. Notably, treatment with nadunolimab reduced tumor growth in mice transplanted with a mixture of BxPC3 and CAFs (N=10 and N=8, p=0.035) but not in mice transplanted with BxPC3 cells only. This study demonstrates that antibody-based blockade of IL1RAP by nadunolimab disrupts interactions between PDAC cells and CAFs resulting in substantial global transcription changes in the CAFs, reduced recruitment of monocytes and decreased PDAC tumor growth in vivo. These findings suggest that targeting IL1RAP has a major impact on the PDAC tumor microenvironment and reveals new anti-tumor mechanisms of nadunolimab treatment. Citation Format: Nils Hansen, Pablo Peña, Finja Hansen, Petter Skoog, Susanne Larsson Faria, Karin von Wachenfeldt, Carl Högberg, Camilla Rydberg Millrud, David Liberg, Marcus Järås. The IL1RAP-blocking antibody nadunolimab disrupts pancreatic cancer cell and fibroblast crosstalk, reduces recruitment of myeloid cells and inhibits tumor growth [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C055.

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Carpenter, Eileen S., Samantha Kemp, Padma Kadiyala, Nina Steele, Ahmed Elhossiny, Stephanie The, Valerie Gunchick, et al. "Abstract PO-098: Longitudinal profiling of pancreatic cancer patients identifies interleukin-8 as a mediator of myeloid-epithelial crosstalk." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—098—PO—098. http://dx.doi.org/10.1158/1538-7445.panca21-po-098.

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Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in the US. A key hallmark of this disease is that, while tumors initially show susceptibility to standard chemotherapeutic agents, most patients eventually develop resistance, leading to poor survival. While the mechanisms of chemoresistance are unclear, murine studies have implicated the myeloid compartment of the tumor immune microenvironment. Correlative data in human tumors supports this notion, however, mechanistic studies are lacking, thus impairing translation to the clinic. The study of human pancreatic cancer has historically been challenging due to difficulty of fresh biospecimen acquisition, patient heterogeneity, and a diverse tumor microenvironment. Moreover, the vast majority of pancreatic cancer patients do not qualify for surgical resection, further limiting tissue availability. We have overcome these difficulties by developing a pipeline to analyze human tumor samples and matched blood using high-fidelity techniques including single-cell RNA sequencing (scRNAseq) and mass cytometry (CyTOF), together with establishment of organoids from the same tumors. Notably, in this pipeline we can use small amounts of tissue from endoscopic fine needle biopsies, thus allowing us to sample tumors from patients at any disease stage. Results: We performed CyTOF on longitudinally-matched peripheral blood mononuclear cells (PBMCs) from 30 patients and single-cell RNA sequencing on 6 patients in the treatment naïve and on-treatment (FOLFIRINOX) state. CyTOF revealed distinct alterations in the myeloid population, with a shift toward CXCR2hiPD-L1hi granulocytes with FOLFIRINOX treatment over time. Analysis of PBMCs from scRNAseq showed a distinct myeloid gene signature with FOLFIRINOX and in particular highlighted interleukin-8 (IL8), a chemokine involved in myeloid cell chemotaxis that is associated with poor prognosis in pancreatic cancer. Further mapping of IL8 in tumor tissue by scRNAseq showed that it is highly expressed in subpopulations of tumor epithelial cells and tumor-infiltrating granulocytes. IL8-high tumor-infiltrating granulocytes also highly expressed VEGF and CXCR4, suggesting immunosuppressive and angiogenic roles. IL8-high tumor epithelial cells were found to have a basal-like phenotype and also expressed a network of other chemokines including CXCL1, CXCL3, CXCL5, which are known to recruit immunosuppressive myeloid cells. Conclusions: Through longitudinal and multimodal mapping using PDAC patient blood and tumor biospecimens, we have identified IL8 as a potential mediator of epithelial-myeloid crosstalk in PDAC chemoresistance and tumor aggression. Validation studies using an all-human co-culture system of PDAC patient-derived organoids and myeloid cells are currently underway. Citation Format: Eileen S. Carpenter, Samantha Kemp, Padma Kadiyala, Nina Steele, Ahmed Elhossiny, Stephanie The, Valerie Gunchick, Rémy Nicolle, Michelle Anderson, Wenting Du, Carlos Espinoza, Richard Kwon, Erik-Jan Wamsteker, Anoop Prabhu, Allison Schulman, Vaibhav Sahai, Timothy Frankel, Filip Bednar, Marina Pasca di Magliano. Longitudinal profiling of pancreatic cancer patients identifies interleukin-8 as a mediator of myeloid-epithelial crosstalk [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-098.

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Thomas, Justin, Molly Torok, Kriti Agrawal, Trang Vu, Alyssa Castillo, Min Chen, Bryan Remaily, et al. "678 The neonatal Fc receptor is elevated in monocyte-derived immune cells in pancreatic cancer." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A706. http://dx.doi.org/10.1136/jitc-2021-sitc2021.678.

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States with 5-year survival rates below 10%. PDAC is commonly diagnosed after metastasis has occurred and treatment options are limited. Immune checkpoint inhibitor (ICI) monoclonal antibody (mAb) therapy has shown great promise in other cancers, however little efficacy has been observed in patients with PDAC. The protein responsible for recycling IgG based mAb therapeutics like ICIs in the bloodstream, as well as processing peptides for antigen presentation, is the neonatal Fc receptor (FcRn). Little is known about FcRn in cancer, and to our knowledge no characterization of host FcRn, or FcRn extrinsic to tumor cells exists in PDAC patients. We hypothesized that PDAC patients and tumor-bearing animals would have altered FcRn expression by their immune populations compared to their healthy counterparts.MethodsC57BL/6 mice were orthotopically injected with KPC-luc (KrasLSL-G12D, Trp53LSL-R270H, Pdx1-cre) pancreatic tumor cells, and FcRn expression in myeloid-derived splenocytes were analyzed by fluorescence cytometry. Time-of-flight mass cytometry (CyTOF) was utilized to immunophenotype peripheral blood mononuclear cells (PBMCs) of PDAC or non-cancer patients for expression levels of FcRn within these immune populations.ResultsPDAC tumor-bearing mice exhibit altered FcRn expression among myeloid immune cell populations. Mice with pancreatic tumors had elevated expression of FcRn on migratory cDC2 (CD8-CD11b+CD103+CD24++; p = 0.017), monocytic MDSC (CD11b+Ly6G-Ly6C+; p = 0.0023), granulocytic MDSC (CD11b+Ly6G+Ly6C±; p = 0.0542), and cDC2 (CD8-CD11b+CD103-CD24±; p=0.036) cells. PBMCs from non-cancer obese patients (healthy control samples; n=8) and PDAC patients prior to surgical resection (n=13) were subjected to CyTOF analyses. The majority of FcRn expression was concentrated to monocyte (p=0.017), DCs (p=0.017) and MDSC (p=0.012) immune populations. Overall, we observed increased expression of FcRn on myeloid-derived immune populations from patients with PDAC. FcRn expression was elevated in both monocytes and DC populations in PDAC relative to non-cancer PBMCs. Monocytic and granulocytic MDSC from patients with PDAC had significantly elevated FcRn positivity compared to healthy controls (p = 0.034, p = 0.026, respectively).ConclusionsFcRn is upregulated in monocytes, dendritic cells and MDSC immune populations in patients and mice with pancreatic tumors. Future investigations into FcRn function in preclinical models and PDAC patients will hopefully elucidate new mechanisms of ICI resistance and possible alternative approaches for improving immunotherapy efficacy in these patients.Ethics ApprovalAll patients provided voluntary written informed consent (Institutional Review Board protocol: 2010C0051) to participate. The protocols and subsequent amendments were approved by The Ohio State University Institutional Review Board. All animal protocols were approved by the Ohio State University Institutional Animal Care and Use Committee (IACUC) at The Ohio State University (Approved IACUC protocols 2009A0178-R4 and 2017A00000117-R1) and mice were treated in accordance with institutional guidelines for animal care. The Ohio State University Laboratory Animal Shared Resource is an Association for Assessment and Accreditation of Laboratory Animal Care International accredited program that follows Public Health Service policy and guidelines. All other experiments were completed under the research protocols (2014R00000086; 2013R00000056) approved by the Ohio State University Institutional Biosafety Committee.

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Rambuscheck, C., P. Metzger, C. Hörth, R. Hennel, S. Bärthel, C. Falcomatà, K. Lauber, et al. "P03.11 Exploring tumor-intrinsic factors regulating the recruitment of myeloid-derived suppressor cells (MDSC) in pancreatic ductal adenocarcinoma." Journal for ImmunoTherapy of Cancer 8, Suppl 2 (October 2020): A26.2—A27. http://dx.doi.org/10.1136/jitc-2020-itoc7.50.

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BackgroundPancreatic Ductal Adenocarcinoma (PDAC) has very poor 5-year overall survival rate. Despite the encouraging effect of immunotherapy in other cancer types, clinical benefit in PDAC patients remains limited. One of the reasons for the lack of success is the immunosuppressive tumor microenvironment (TME), which is maintained by myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages. High MDSC infiltration is associated with a poor survival in PDAC patients. Our project aims at identifying tumor-driven chemokines that influence recruitment of MDSC and establishment of the immunosuppressive tumor microenvironment.Materials and Methods45 PDAC cell lines generated from spontaneous tumors of genetically-modified mice harboring the characteristic driver mutations KrasG12D or PIK3CAH1047R were analyzed for their expression levels of CXCL1, CCL2, G-CSF and GM-CSF by qRT-PCR. In order to study the relationship between the chemokine/cytokine profile and the immune cell infiltration, selected tumor cell lines were implanted orthotopically in C57BL6 mice. Three weeks after inoculation blood, spleen and tumor were isolated and organ specific immune cell infiltration was analyzed by flow cytometry. To further characterize tumor-secreted factors tumor conditioned medium was generated and the concentration of 33 chemokines was analyzed in a multiplex assay. The chemokine levels were correlated with migratory capacity of splenic MDSC measured in an ex vivo chemotaxis assay.ResultsCXCL1 significantly enhanced migration of polymorphonuclear MDSC (PMN-MDSC) in vitro, while migration of monocytic MDSC (M-MDSC) was predominantly skewed towards CCL2. Three weeks after tumor inoculation, MDSC populations in blood and spleen were expanded. Most intriguingly, PDAC cell lines with high CXCL1 or CCL2 levels in vitro showed significantly enriched intratumoral accumulation of PMN-MDSC and M-MDSC, respectively, suggesting that tumor-intrinsic chemokine secretion and not factors from the tumor stroma determined MDSC infiltration. The ex vivo chemotaxis assays revealed additional factors that modulate migration of MDSC into the TME.ConclusionsThe in vitro gene expression levels of individual chemokines (CXCL1 and CCL2) determines the MDSC infiltration in vivo into the TME. Targeting the chemokine-receptor axis of MDSC subpopulations could be a promising approach in the treatment of pancreatic cancer.FundingThe project was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Projektnummer 329628492 - SFB 1321 and the Förderprogramm für Forschung und Lehre (FöFoLe) funded by the Ludwig-Maximilians-Universität München.Disclosure InformationC. Rambuscheck: None. P. Metzger: None. C. Hörth: None. R. Hennel: None. S. Bärthel: None. C. Falcomatà: None. K. Lauber: None. S. Endres: None. D. Saur: None. M. Schnurr: None. L.M. König: None.

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Shao, Xuejun, Shenghao Hua, Tao Feng, Dickson Kofi Wiredu Ocansey, and Lei Yin. "Hypoxia-Regulated Tumor-Derived Exosomes and Tumor Progression: A Focus on Immune Evasion." International Journal of Molecular Sciences 23, no. 19 (October 4, 2022): 11789. http://dx.doi.org/10.3390/ijms231911789.

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Tumor cells express a high quantity of exosomes packaged with unique cargos under hypoxia, an important characteristic feature in solid tumors. These hypoxic tumor-derived exosomes are, crucially, involved in the interaction of cancer cells with their microenvironment, facilitating not only immune evasion, but increased cell growth and survival, enhanced angiogenesis, epithelial–mesenchymal transition (EMT), therapeutic resistance, autophagy, pre-metastasis, and metastasis. This paper explores the tumor microenvironment (TME) remodeling effects of hypoxic tumor-derived exosome towards facilitating the tumor progression process, particularly, the modulatory role of these factors on tumor cell immune evasion through suppression of immune cells, expression of surface recognition molecules, and secretion of antitumor soluble factor. Tumor-expressed exosomes educate immune effector cells, including macrophages, monocytes, T cells, natural killer (NK) cells, dendritic cells (DCs), γδ T lymphocytes, regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), mast cells, and B cells, within the hypoxic TME through the release of factors that regulate their recruitment, phenotype, and function. Thus, both hypoxia and tumor-derived exosomes modulate immune cells, growth factors, cytokines, receptor molecules, and other soluble factors, which, together, collaborate to form the immune-suppressive milieu of the tumor environment. Exploring the contribution of exosomal cargos, such as RNAs and proteins, as indispensable players in the cross-talk within the hypoxic tumor microenvironmental provides a potential target for antitumor immunity or subverting immune evasion and enhancing tumor therapies.

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Jin, Lin, Jing Yang, Zhujun Yi, Hong S. Kim, Feng Tian, and Jiaqi Shi. "Abstract PO-125: The role of KDM6A in pancreatic cancer immune microenvironment." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—125—PO—125. http://dx.doi.org/10.1158/1538-7445.panca21-po-125.

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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States, with a 10% 5-year survival rate. Immunosuppressive myeloid cells, including tumor-associated neutrophils (TANs), contribute to tumor development and treatment resistance. Lysine (K)-specific demethylase 6A (KDM6A) is one of the most frequently mutated epigenetic genes and a tumor suppressor in PDAC. However, the molecular mechanisms by which KDM6A contributes to PDAC development and whether KDM6A impacts the tumor immune microenvironment are unknown. This study established a genetically engineered pancreas-specific Kdm6a-knockout Ptf1aCre;LSL-KrasG12D/+;LSL-p53R172H/+ (KPC) PDAC mouse model to investigate the influence of KDM6A loss on PDAC development and tumor immune microenvironment. We found that KDM6A loss accelerated PDAC progression and increased metastases. Pancreata of mice with Kdm6a deficiency developed aggressive undifferentiated PDACs. Additionally, KDM6A loss led to increased infiltration of TANs and neutrophil extracellular traps (NETs) formation. Mechanistically, we used Bru-seq technology to investigate the impact of KDM6A on nascent RNA transcription. We demonstrated that many chemotactic cytokines related to neutrophil recruitment, specifically CXCL1, were upregulated in KDM6A-knockout PDAC cells. We further confirmed increased CXCL1 mRNA and protein levels in KDM6A-deficient human and mouse PDAC cells. In addition, immunohistochemical staining also confirmed the upregulated CXCL1 expression in both human and murine PDAC cells with KDM6A loss. TANs were found to express CXCR2, the receptor of CXCL1, by immunofluorescent analysis. To further confirm that cancer cells with KDM6A loss can attract neutrophils in vitro, we performed chemotaxis assays using both human neutrophils derived from PLB-985 cells and mouse primary neutrophils isolated from bone marrow and conditioned media from KDM6A- knockout or knockdown PDAC cells. We found that PDAC cells with KDM6A loss promoted neutrophil recruitment in vitro compared to KDM6A-retained PDAC cells. Furthermore, the CXCL1 neutralizing antibody reversed the chemotactic property of KDM6A-deficient PDAC cells, confirming that CXCL1 is the primary chemokine mediating the neutrophil recruitment. In summary, these findings shed light on the mechanism by which KDM6A loss promotes PDAC development, regulates tumor immune microenvironment, and suggests that the CXCL1-CXCR2 axis may be a candidate target for the treatment of PDAC, especially those with KDM6A mutations. Citation Format: Lin Jin, Jing Yang, Zhujun Yi, Hong S. Kim, Feng Tian, Jiaqi Shi. The role of KDM6A in pancreatic cancer immune microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-125.

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