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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 (octubre de 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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Mahadevan, Daruka, Ritu Pandey, Yuliang Chen, Jacob Essif y Aisha Al-Khinji. "Oncogenic roles of CEACAM6 in pancreatic ductal adenocarcinoma." Journal of Clinical Oncology 38, n.º 15_suppl (20 de mayo de 2020): e16744-e16744. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16744.
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e16744 Background: Carcinoembryonic cell adhesion molecule 6 (CEACAM6) is a cell adhesion receptor of the Ig-superfamily overexpressed in human Pancreatic Ductal Adenocarcinoma (PDA), enriching to the classical activated stroma subtype. CEACAM6 has multifaceted roles in PDA and is a poor prognostic maker (Pandey et al. Sci Rep 2019). We report functional correlative studies across PDA cell lines with high vs KO vs low of CEACAM6 and a PDX model with a therapeutic Mab. Methods: RNA-Seq and microarray expression data of PDA cell lines were downloaded from GEO using R (4.3), normalized and log transformed for analysis: CEACAM6 high vs. low were assessed for differential gene expression changes. Correlation of CEACAM6 levels with genes of interest was studied and compared with the CEACAM6 KO proteomic profile of HPAF-II cells. CEACAM6 WT vs. KO cells were profiled for protein kinase (PK) activity (PAMChip) and gene expression changes by RNA-Seq. NSG-CD34+ mice bearing PDX were evaluated with a humanized anti-CEACAM6 Mab for anti-tumor activity. Results: Differential expression analyses between PDA cell lines with low vs KO vs high CEACAM6 resulted in identifying similar markers changing in quantitative proteomics. KRT20, SYTL1, SKIL, CES1P1, MAN1A1 were down-regulated and HMOX1, CPNE2, ABCD1 were up-regulated in CEACAM6 low or KO cell lines. Specific PKs are upregulated in CEACAM6 KO enriching to the TK family (EPH A1, 3, 4, 8 and HCK), AGC family (e.g. AKT, PKA) and cellular apoptosis (e.g. BAD). RNA-Seq of CEACAM6 WT vs KO cells reconfirmed the up-regulation of MMP1, IL2RG, ATP6V0D2 and low expression of KRT20, AGK and MAN1A1 in CEACAM6 KO cells. Pharmacologic inhibition with a humanized anti-CEACAM6 scFv-Fc (IgG4) in PDA PDX of NSG CD34+ mice demonstrated ~55% tumor growth inhibition (TGI) with enhanced survival of > 14 days vs. control. Conclusions: CEACAM6 is expressed exclusively in primates and humans and plays multifaceted oncogenic roles in PDA pathogenesis. When CEACAM6 is disrupted, ECM proteins are altered reshaping the stroma, activating specific PKs and priming apoptosis. The therapeutic anti-CEACAM6 Mab possesses anti-tumor activity with associated cellular apoptosis and increased mouse survival.
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Metzger, Philipp, Sabrina V. Kirchleitner, Daniel F. R. Boehmer, Christine Hörth, Angelika Eisele, Steffen Ormanns, Matthias Gunzer et al. "Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model". Cancer Immunology, Immunotherapy 69, n.º 10 (24 de mayo de 2020): 2101–12. http://dx.doi.org/10.1007/s00262-020-02605-9.
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Abstract Pancreatic ductal adenocarcinoma is characterized by a strong immunosuppressive network with a dense infiltration of myeloid cells including myeloid-derived suppressor cells (MDSC). Two distinct populations of MDSC have been defined: polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC). Several factors influence the development and function of MDSC including the transcription factor interferon regulatory factor 4 (IRF4). Here, we show that IRF4 deficiency accelerates tumor growth and reduces survival, accompanied with a dense tumor infiltration with PMN-MDSC and reduced numbers of CD8+ T cells. As IRF4 has been described to modulate myeloid cell development and function, particularly of PMN-MDSC, we analyzed its role using MDSC-specific IRF4 knockout mice with the Ly6G or LysM knock-in allele expressing Cre recombinase and Irf4flox. In GM-CSF-driven bone marrow cultures, IRF4 deficiency increased the frequency of MDSC-like cells with a strong T cell suppressive capacity. Myeloid (LysM)-specific depletion of IRF4 led to increased tumor weight and a moderate splenic M-MDSC expansion in tumor-bearing mice. PMN cell (Ly6G)-specific depletion of IRF4, however, did not influence tumor progression or MDSC accumulation in vivo in accordance with our finding that IRF4 is not expressed in PMN-MDSC. This study demonstrates a critical role of IRF4 in the generation of an immunosuppressive tumor microenvironment in pancreatic cancer, which is independent of IRF4 expression in PMN-MDSC.
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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, n.º 1 (junio de 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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Cappello, Paola, Moitza Principe, Michelle Samuel Chattaragada, Roberta Curto, Daniele Giordano, Cecilia Roux y Francesco Novelli. "The surface alpha-enolase targeting as a novel immunotherapeutical strategy for pancreatic cancer". Journal of Immunology 196, n.º 1_Supplement (1 de mayo de 2016): 75.20. http://dx.doi.org/10.4049/jimmunol.196.supp.75.20.
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Abstract Pancreatic Ductal Adenocarcinoma (PDA) is a very aggressive tumor for which effective therapeutical strategies are still lacking. The global five-years survival is of 5% and surgery is the only potentially curative treatment. The PDA-associated antigen α-enolase (ENO1), beside its glycolytic function, acts as a plasminogen receptor, promoting activation into plasmin, involved in extracellular matrix degradation. Antibodies against ENO1 are detected in more than 60% of PDA patients and correlate with a better prognosis. Furthermore, anti-ENO1 antibodies are induced in mice after ENO1-DNA vaccination. We observed an increased ENO1 expression on the cell surface of both PDA and myeloid cells (MDSC), suggesting a role in tumor progression and spreading. The immunotherapy represents a chance to selectively target PDA cells and MDSC. Mouse anti-human ENO1 monoclonal antibody (mAb) inhibits plasminogen-dependent invasion of human PDA cells and metastatic spreading in immunosuppressed mice, as well as MDSC adhesion to pancreatic endothelial cells and in vitro and in vivo migration. Similarly MDSC arginase activity and secretion of IL-6 decrease after ENO1 triggering, while anti-ENO1 treatment does not affect costimulatory molecule expression and MDSC suppression functions. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing an anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDA cells. In conclusion, the antibodies anti-ENO1 may inhibit PDA cell and myeloid cell invasion and modulate T cell response, making the immunotherapy more effective.
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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, n.º 3 (22 de marzo de 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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Bianchi, Anna, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido et al. "Abstract 2513: MDSC-derived TNF is a novel regulator of T-cell dysfunction in pancreatic cancer". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 2513. http://dx.doi.org/10.1158/1538-7445.am2022-2513.
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Abstract Introduction: Abundance of myeloid-derived suppressor cells (MDSC) and a dysfunctional T-cell compartment are defining hallmarks of therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC). Using congenic in vivo murine models to phenocopy extremes of T-cell enrichment or exclusion, we sought to interrogate central MDSC-mediated mechanisms that govern immune tolerance in PDAC. Methods: Orthotopically implanted T-cell-excluded (Tcelllo) vs T-cell-enriched (T-cellhi) congenic KPC tumors, and intratumoral Ly6G+F4/80- MDSCs from both clones, were subjected to RNA sequencing. Ex vivo co-cultures evaluated the effects of intratumoral MDSC on splenic T-cells. Orthotopically injected KPC-T-celllo mice were treated with etanercept vs. vehicle, and immunophenotyping via flow cytometry was performed. Results: RNA-seq of KPC T-celllo vs. T-cellhi tumors revealed enrichment of myeloid immunoregulatory pathways, and downregulation of leukocyte activation/cytotoxicity pathways. Flow cytometry revealed a dramatic increase in MDSCs infiltrating KPC-Tcelllo tumors (P<0.001). To decipher MDSC-intrinsic mechanisms associated with T-cell exclusion, RNA-seq of MDSCs infiltrating T-cellhi clones revealed relative downregulation of MAPK signaling, and cytokine profiling of MDSCs conditioned with MAPK inhibitor trametinib revealed marked reduction in TNF secretion. Confocal microscopy confirmed striking decrease in TNF in MDSCs isolated from KPC- T-cellhi vs. Tcelllo tumors. Ex vivo MDSC-T-cell co-cultures significantly attenuated T-cell proliferation and activation (via IFN-γ release) while favoring T-cell apoptosis, which could be rescued by pre-conditioning MDSCs with either etanercept (TNFR2 decoy receptor) or MAPK pathway inhibitors. Orthotopically injected KPC-T-celllo tumor-bearing mice treated with etanercept demonstrated a remodeled TME vs. vehicle-treated mice, with attenuation in MDSC trafficking, enrichment in CD4+/CD8+ T-cell infiltration, and reduction in T-cell exhaustion. Conclusion: MDSC-derived TNF regulates T-cell dysfunction in PDAC via a MAPK-dependent mechanism. Compartment-specific inhibition of TNF may be a provocative strategy to overcome immune tolerance in PDAC. Citation Format: Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Siddharth Mehra, Samara Singh, Austin R. Dosch, Vanessa T. Garrido, Christine I. Rafie, Nagaraj Nagathihalli, Nipun Merchant, Jashodeep Datta. MDSC-derived TNF is a novel regulator of T-cell dysfunction 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 2513.
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Wen, Hui-Ju, Jacee Moore, Erick Davis, Daniel Long, Justin Lee, Brian Devorkin y Howard Crawford. "Abstract B080: Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of pancreatic ductal adenocarcinoma". Cancer Research 82, n.º 22_Supplement (15 de noviembre de 2022): B080. http://dx.doi.org/10.1158/1538-7445.panca22-b080.
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Abstract Activation of cellular signaling pathways by crosstalk between tumor cells and their microenvironment is an essential mechanism supporting pancreatic carcinogenesis. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Systemic blockade of ADAM17 significantly reduced tumor burden and suppressed activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways. In addition, we found an elevated level of CCL21 in the MEDI3622-treated tumors resulting in increased tumor infiltration by dendritic cells and cytotoxic T cells as well as low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). These results demonstrate a pronounced anti-tumor effect by ADAM17 blockade and indicate ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Jacee Moore, Erick Davis, Daniel Long, Justin Lee, Brian Devorkin, Howard Crawford. Disruption of ADAM17-dependent cellular crosstalk inhibits tumor progression of 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 B080.
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Wen, Hui-Ju y Howard Crawford. "Abstract 341: Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 341. http://dx.doi.org/10.1158/1538-7445.am2022-341.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and will become the 2nd leading cause of cancer related death in the United States within the next 10 years. Lack of early symptoms and a poor response to current therapies make PDAC the deadliest of all major cancers. PDAC is characterized by a dense fibroinflammatory stroma which is composed of fibroblasts and immune cells and has been implicated to influence tumor progression and therapeutic outcome. In this study, we aim to disrupt cellular signaling pathways by targeting ADAM17 (a disintegrin and metalloprotease 17). ADAM17 is a membrane bound enzyme which cleaves cell surface proteins. Its function is closely linked with autocrine and paracrine signaling of immunomodulation as well as activation of EGFR, which is a central molecule for pancreatic tumorigenesis. To investigate whether EGFR is activated via a paracrine manner from macrophages, the most abundant immune-related stromal cells in pancreas cancers, we generated a pancreatic tumor mouse model with ADAM17 deletion in myeloid cells by using a dual recombinase strategy. We observed that lack of ADAM17 in the myeloid cells resulted in a delay of acinar cell transformation and an associated decrease in EGFR activation. To further examine the tumor supportive role of ADAM17, systemic inhibition of ADAM17 using anti-ADAM17 antibody, MEDI3622, was tested in orthotopic tumor bearing mice. Tumor regression was observed in the mice treated with MEDI3622 and was accompanied by high infiltration of cytotoxic T cells and low infiltration of G-MDSC (granulocytic myeloid-derived suppressor cells). In addition, activation of EGFR and STAT3, which are associated with two pro-tumoral signaling pathways, were reduced by MEDI3622. These results demonstrate a pronounced anti-tumor effect by ADAM17 blockage and indicate ADAM17 as a therapeutic target of pancreatic cancer. Citation Format: Hui-Ju Wen, Howard Crawford. Disruption of cellular crosstalk by blockage of ADAM17 inhibits tumor progression of pancreatic ductal adenocarcinoma [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 341.
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Fulton, Alexander J. P., Kourosh Saeb-Parsy y Bristi Basu. "Abstract A074: Developing a novel in vivo model of pancreatic ductal adenocarcinoma using primary tumor samples and humanised mouse models". Cancer Research 82, n.º 22_Supplement (15 de noviembre de 2022): A074. http://dx.doi.org/10.1158/1538-7445.panca22-a074.
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Abstract Pancreatic cancer (PDAC) remains one of the most lethal malignancies due to its late diagnosis and poor response to treatment. Preclinical models reflecting the uniquely complex structure of PDAC cells and the surrounding tumor microenvironment (TME) are required to ensure translational results. PDAC organoids, ex vivo 3D models of primary tumor cells, form an exciting preclinical model that reflects the complexity of PDAC. Tumor organoids co-cultured with stromal and immune cells have been previously explored in vitro but have thus far remained limited in any in vivo capacity. We therefore aimed to establish and characterize in vitro co-cultured PDAC organoids using primary human PDAC tumor samples plus autologous peripheral or splenic lymphocytes. Subsequent preliminary in vivo models have been established by engrafting co-cultured PDAC organoids and PDAC cancer associated fibroblasts into immunocompromised mice. The pilot data assessed retention, growth kinetics and metastatic potential and will subsequently form the foundation for comparable experiments using autologous humanized mouse models. This humanized mouse model, consisting of autologous human malignant, stromal and immune compartments, will add to the existing repertoire of preclinical models by more closely representing the entire tumor volume. In vitro and in vivo data compared to other preclinical models. Additional preliminary therapeutic response data may provide translational value and warrant further evaluation. Citation Format: Alexander J. P. Fulton, Kourosh Saeb-Parsy, Bristi Basu. Developing a novel in vivo model of pancreatic ductal adenocarcinoma using primary tumor samples and humanised mouse models [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 A074.
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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 (noviembre de 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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Thomas, Justin, Molly A. Torok, Kriti Agrawal, Timothy Pfau, Trang T. Vu, Justin Lyberger, Hsiaochi Chang et al. "The Neonatal Fc Receptor Is Elevated in Monocyte-Derived Immune Cells in Pancreatic Cancer". International Journal of Molecular Sciences 23, n.º 13 (25 de junio de 2022): 7066. http://dx.doi.org/10.3390/ijms23137066.
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The neonatal Fc receptor (FcRn) is responsible for recycling of IgG antibodies and albumin throughout the body. This mechanism has been exploited for pharmaceutic delivery across an array of diseases to either enhance or diminish this function. Monoclonal antibodies and albumin-bound nanoparticles are examples of FcRn-dependent anti-cancer therapeutics. Despite its importance in drug delivery, little is known about FcRn expression in circulating immune cells. Through time-of-flight mass cytometry (CyTOF) we were able to characterize FcRn expression in peripheral blood mononuclear cell (PBMC) populations of pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer donors. Furthermore, we were able to replicate these findings in an orthotopic murine model of PDAC. Altogether, we found that in both patients and mice with PDAC, FcRn was elevated in migratory and resident classical dendritic cell type 2 (cDC2) as well as monocytic and granulocytic myeloid-derived suppressor cell (MDSC) populations compared to tumor-free controls. Furthermore, PBMCs from PDAC patients had elevated monocyte, dendritic cells and MDSCs relative to non-cancer donor PBMCs. Future investigations into FcRn activity may further elucidate possible mechanisms of poor efficacy of antibody immunotherapies in patients with PDAC.
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Mukherjee, Debasmita, Lena Bercz, Liliana D’Alesio, Jessica Wedig, Timothy Pfau, Molly Torok, Shrina Jasani y Thomas A. Mace. "Abstract B077: Tomatidine targets ATF4-dependent signaling to limit pancreatic cancer in the tumor microenvironment". Cancer Research 82, n.º 22_Supplement (15 de noviembre de 2022): B077. http://dx.doi.org/10.1158/1538-7445.panca22-b077.
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Abstract Background: Pancreatic ductal adenocarcinoma (PDAC), comprising of 90% pancreatic cancer malignancies, is a highly aggressive cancer with a five-year survival rate of 10.8%. Current therapies include surgical resection and chemotherapy, which are mostly ineffective because of metastasis and an immunosuppressive tumor microenvironment (TME). Tomatidine, a natural metabolite present in the tomato plant, has anti-cancer and anti-inflammatory properties. Further, tomatidine has been reported to possibly correlate with inhibition of Activating Transcription Factor 4 (ATF4)-dependent signaling in multiple diseases such as skeletal muscle atrophy and dengue virus infection. ATF4, a master regulator of cellular stress, has been implicated in different cancers including PDAC by promoting cell survival, inducing resistance towards commonly used chemotherapeutic agents as well as by affecting anti-tumor immunity. Hypothesis: We hypothesize that tomatidine can inhibit pancreatic cancer by regulating ATF4-dependent signaling. Methods: Pancreatic tumor cell lines were assayed for cell growth after tomatidine treatment. Subcutaneous tumor-bearing C57BL/6 mice and athymic mice were treated with 5 mg/kg daily i.p. injections of tomatidine or vehicle. Orthotopic tumor bearing C57BL/6 mice were treated with either 5 mg/kg tomatidine daily alone, 10 mg/kg gemcitabine twice per week alone or both in combination, respectively via i.p. injections and assessed in comparison to vehicle. To assess ATF4-dependent signaling, protein and RNA expression of ATF4 and related genes as well as binding activity of ATF4 was evaluated via immunoblotting, Q-PCR analysis and chromatin immunoprecipitation. Further, healthy donor PBMCs were treated with tomatidine in presence of cytokines to observe myeloid derived suppressor cell (MDSC) differentiation. Results: We found that tomatidine can inhibit pancreatic tumor growth in vitro and in vivo. Tomatidine also enhanced the gemcitabine chemosensitivity in an orthotopic model of pancreatic cancer in vivo. However, there was little effect of tomatidine on tumor growth when pancreatic cancer cells were implanted into athymic mice, suggesting tomatidine may affect anti-tumor immunity. Tomatidine reduced phosphorylation of 4EBP1 (downstream of ATF4) in vitro and reduced mRNA expression of ATF4 and eIF4EBP1 in MT5 tumor-bearing mice treated with tomatidine. Further, tomatidine reduced the transcriptional binding activity of ATF4 with downstream genes such as eIF4EBP1. Tomatidine affected the rate of MDSC differentiation and reduced expression of ATF4 and related gene expression in immune cells. Conclusion: This study sheds light on tomatidine, a novel plant derived anti-cancer treatment that targets an upregulated pathway (ATF4 dependent signaling) in pancreatic cancer and can therefore be used to develop a novel therapeutic against the pancreatic tumor as well as its microenvironment. Citation Format: Debasmita Mukherjee, Lena Bercz, Liliana D’Alesio, Jessica Wedig, Timothy Pfau, Molly Torok, Shrina Jasani, Thomas A. Mace. Tomatidine targets ATF4-dependent signaling to limit pancreatic cancer 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 B077.
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Deshpande, Nilesh, Anna Bianchi, Iago De Castro Silva, Vanessa Garrido, Siddharth Mehra, Samara Singh, Ifeanyichukwu Ogobuiro, Nagaraj Nagathihalli, Nipun B. Merchant y Jashodeep Datta. "Abstract C031: Targeting granulocytic MDSC-derived inflammasome activation to overcome stromal inflammation in pancreatic cancer". Cancer Research 82, n.º 22_Supplement (15 de noviembre de 2022): C031. http://dx.doi.org/10.1158/1538-7445.panca22-c031.
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Abstract Objective: The major drivers of therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) are myeloid cell-derived signaling that sustains immune tolerance/exclusion, and interleukin-1 (IL-1)-mediated inflammatory polarization of cancer-associated fibroblasts (iCAF) which promotes stromal inflammation by elaborating soluble factors (i.e., CXCL1, IL-6) that further accelerate myeloid chemotaxis. Moreover, we have recently shown that enrichment of pathways related to inflammasome activation-which involves recruitment of ASC complexes culminating in IL-1β generation—is a major contributor to chemoresistance in advanced PDAC patients. However, how these disparate pathways converge to mediate stromal inflammation in PDAC is incompletely understood. Methods: Single-cell RNA sequencing (scRNAseq) and caspase-1 luminescence assays in human and genetically engineered mouse (GEM) PDAC models were interrogated to identify cellular source of inflammasome-derived IL-1β. Gene set enrichment analysis in bulk RNA-sequencing data and signal transduction studies examined novel pathways associated with inflammasome activation in granulocytic myeloid-derived suppressor cells (gMDSC). scRNAseq and ASC-speck formation via confocal microscopy in intratumoral gMDSCs was performed in PKT mice treated with a novel anti-ASC antibody. Results: scRNAseq in human and GEM PDAC models revealed gMDSCs as the dominant source of inflammasome activation-derived IL1B expression. Functionally, caspase-1 activation and ASC-speck formation was strongest in intratumoral gMDSCs, compared with tumor-cell, CAF, macrophage, T-cell, and dendritic cell, compartments. Investigating developmental trajectories of single-cell transcriptomes in intratumoral gMDSCs from Panc02 tumors revealed an activated Cd14+ gMDSC state with strong co-expression of Cxcr2 and Il1b. As such, treatment of PKT GEM and orthotopically injected KPC tumor-bearing mice with CXCR2 inhibitor AZD5069 significantly abrogated inflammasome activation in intratumoral and splenic gMDSCs. In vitro signal transduction and RNA-seq studies revealed cooperativity between Tlr4-Myd88 and Cxcr2-Tpl2-p38 signaling in activating gMDSC-restricted inflammasome signaling. Co-culture of intratumoral gMDSCs and KPC CAFs ex vivo revealed strong induction of CAF-intrinsic Il6/Cxcl1 expression, which was dependent in part on CAF-Il1r1 expression and inflammasome activation in gMDSCs. We next used antibody to target ASC-a common downstream adaptor complex inducing inflammasomes-in vivo. Treatment of PKT mice with this anti-ASC antibody significantly attenuated ASC-speck formation in intratumoral gMDSCs as well as CAF-specific Il6/Cxcl1 expression via scRNAseq. Conclusions: These data uncover granulocytic MDSCs as the dominant source of inflammasome activation derived-IL1β in the PDAC TME, which promotes stromal inflammation via iCAF polarization. Therapeutic approaches-such as anti-ASC treatment-targeting gMDSC-intrinsic inflammasome activation may mitigate stromal inflammation and overcome therapeutic resistance in PDAC. Citation Format: Nilesh Deshpande, Anna Bianchi, Iago De Castro Silva, Vanessa Garrido, Siddharth Mehra, Samara Singh, Ifeanyichukwu Ogobuiro, Nagaraj Nagathihalli, Nipun B. Merchant, Jashodeep Datta. Targeting granulocytic MDSC-derived inflammasome activation to overcome stromal inflammation in pancreatic cancer [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 C031.
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Boda, Akash, Casey Ager, Kimal Rajapakshe, Spencer Lea, Maria Emilia Di Francesco, Philip Jones y Michael Curran. "758 High-potency synthetic STING agonists rewire the myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic ductal adenocarcinoma". Journal for ImmunoTherapy of Cancer 9, Suppl 2 (noviembre de 2021): A793. http://dx.doi.org/10.1136/jitc-2021-sitc2021.758.
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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is clinically unresponsive to immune checkpoint blockade (ICB) immunotherapy.1 2 High densities of immunosuppressive myeloid cells,3 a paucity of antigen-presenting cells4–6 and T cell exclusion from tumour microenvironment7 all contribute to the refractory nature of PDAC to immune-based therapies. We and others have shown that innate immune activation of myeloid stroma via engagement of the STING (Stimulator of Interferon Genes) pathway can mediate proinflammatory remodeling and trigger a flood of T cell infiltration into otherwise 'cold' tumours.8–11 To that end, intratumoral injection of cyclic dinucleotide (CDN) agonists of the STING pathway has been shown to foster local and abscopal tumor immunity.8–10 Despite proven therapeutic efficacy in preclinical models, the mechanistic basis at a cellular level of how CDNs reprogram the suppressive myeloid stroma to sensitise tumours to ICB is poorly understood.MethodsUsing RNA sequencing and protein arrays we profiled myeloid-derived suppressor cell (MDSC) and M2 macrophage function following stimulation with CDNs of ascending potency. We describe the effects of CDN STING agonists on cell cycle dynamics, metabolic reprogramming and c-Myc expression in MDSCs. Next, in an orthotopic Kras+/G12DTP53+/R172HPdx1-Cre (KPC)-derived model of PDAC, we determined the ability of intratumorally-administered CDNs to sensitise PDAC to checkpoint blockade using bioluminescent in vivo imaging and multi-parameter flow cytometry of tumor stroma post-therapy.ResultsMulti-omics profiling of MDSCs and M2 Macrophages of human and murine origin show that high-potency synthetic STING agonists rewire these populations from immunosuppressive to immune-permissive phenotypes in part through inhibition of c-Myc signaling, energy metabolic modulation, and antagonism of cell cycle. Intratumoral injection of the STING agonist, IACS-8803 resulted in an amplified therapeutic response to checkpoint blockade that was dependent on T/NK cell infiltration into the tumour. Furthermore, dimensionality reduction analyses of multiparameter flow cytometry data show proinflammatory remodeling of the myeloid stroma and enhanced T cell function as salient features of synthetic agonists versus natural CDNs in orchestrating the in vivo therapeutic benefit.ConclusionsThis study uncovers molecular and cellular mechanisms by which STING agonists drive proinflammatory conversion of tumour myeloid stroma. We are the first to report that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization through altering energy metabolism and c-Myc signalling. Lastly, we demonstrate the potential for high-potency STING agonists to overcome resistance to checkpoint blockade in an aggressive orthotopic tumour model of PDAC.ReferencesRoyal RE, Levy C, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33(8):828–33.Brahmer JR, Tykodi SS, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455–65.Karakhanova S, Link J. Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells. Oncoimmunology 2015;4:e998519.Dallal RM, Christakos P, et al. Paucity of dendritic cells in pancreatic cancer. Surgery 2002;131:135–138.Yamamoto T, Yanagimoto H, et al. Circulating myeloid dendritic cells as prognostic factors in patients with pancreatic cancer who have undergone surgical resection. J Surg Res 2012;173:299–308.Hegde S, Krisnawan V, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 2020;37(3):289–307.Beatty GL, Winograd R, et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 2015;149(1):201–210.Baird JR, Friedman D, et al. Radiotherapy combined with novel STING-Targeting oligonucleotides results in regression of established tumors. Cancer Res 2016;76(1):50–61.Ager CR, Reilley MJ, et al. Intratumoral STING activation with T-cell checkpoint modulation generates systemic antitumor immunity. Cancer Immunol Res 2017;5(8):676–84.Smith TT, Moffett HF, et al. Biopolymers codelivering engineered T cells and STING agonists can eliminate heterogeneous tumors. J Clin Invest 2017;127(6):2176–91.Jing W, McAllister D, et al. STING agonist inflames the pancreatic cancer immune microenvironment and reduces tumor burden in mouse models. J Immunother Cancer 2019;7(1):115.
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Venepalli, Neeta K., Chintan Chandrakant Gandhi, Howard Ozer, Dominic Ho, Yang Lu, Hui Xie, Stephanie A. Berg et al. "Phase Ib study of PGG beta glucan in combination with anti-MUC1 antibody (BTH1704) and gemcitabine for the treatment of advanced pancreatic cancer." Journal of Clinical Oncology 33, n.º 3_suppl (20 de enero de 2015): TPS493. http://dx.doi.org/10.1200/jco.2015.33.3_suppl.tps493.
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TPS493 Background: Mucin 1 (MUC1) is a tumor associated membrane-bound glycoprotein that promotes oncogenesis through promotion of epithelial cell polarity loss, anti-apoptosis, and hypoxia driven angiogenesis. MUC1 overexpression is associated with aggressive behavior and poor outcomes in pancreatic ductal adenocarcinoma (PDAC), and increased resistance to gemcitabine (G) in vitro. BTH1704 (BTH) is a humanized monoclonal antibody (MAb) targeting aberrantly glycosylated MUC1. Imprime PGG (PGG) is a soluble yeast-derived b 1,3/1,6 glucan that binds complement receptor 3 (CR3) on innate immune cells priming them to exert anti-tumor activity against complement (iC3b) opsonized tumor cells. Following incubation of PGG with whole blood from healthy subjects, variability in PGG binding to neutrophils and monocytes has been observed, with higher binding and functional changes correlating with higher levels of endogenous anti-b glucan antibodies. BTH binds to antigens (MUC1), leading to iC3b opsonization of tumor cells thus, allowing PGG-primed leukocytes to kill the iC3b-opsonized tumor cells. This forms the rationale for testing BTH1704 combined with G + PGG. Methods: This is a single institution Phase 1b dose escalation study with a standard 3x3 design to determine the maximal administered dose (MAD) of BTH combined with G + PGG in patients with previously treated advanced PDAC.Each dose cohort includes at least one subject with high and one low PGG binding capability. Primary objectives: establish MAD of BTH combined with G + PGG. Secondary objectives: characterize adverse effects, clinical response, time to progression, progression free and overall survival. Correlative objectives: quantify PGG binding, MDSC phenotyping of PBMC, anti b glucan antibody levels, MUC1 IHC. Inclusion criteria: confirmed advanced PDAC, ECOG PS 0-2, rest period 2-6 weeks from prior first- or second-line treatment. Exclusion criteria: uncontrolled chronic illness. Administration and design: BTH and PGG are administered on days 1, 8, 15, and 22 of a 28-day cycle; G is administered on days 1, 8, and 15. The study is currently enrolling patients. Clinical trial information: NCT02132403. Clinical trial information: NCT02132403.
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Kim, Hyejung, Emanuela Guerra, Eunji Baek, Yeojin Jeong, Hyogeun You, Byeongjun Yu, Taeik Jang, Alberti Saverio, Chul-Woong Chung y Changsik Park. "Abstract 328: LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 328. http://dx.doi.org/10.1158/1538-7445.am2022-328.
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Abstract LCB84 is a human Trop-2-targeting antibody drug conjugate (ADC) composed of monomethyl auristatin E (MMAE) as payload and the Hu2G10 (by Mediterranea Theranostic) humanized IgG1 antibody that selectively targets the ADAM10-activated Trop-2 protein selectively expressed in transformed cancer cells (1). LCB84 was prepared using ConjuAll࣪, a proprietary site-directed conjugation technology of LegoChem Biosciences, which incorporates a conjugation ‘handle’ joined by enzymatic prenylation to a specifically engineered recognition sequence (CaaX) on antibody light chains. This conjugation handle facilitates simple versatile chemical conjugation to the linker-payload. A proprietary plasma-stable cleavable linker that is recognized and cleaved by a cancer-associated lysosomal enzyme, β-glucuronidase, was used to enable efficient and traceless payload release in a cancer-specific manner. LCB84 has been evaluated for anti-tumor activity and showed superior anticancer efficacy in triple-negative breast cancer (TNBC), pancreatic ductal adenocarcinoma (PDAC), gastric cancer and non-small cell lung cancer (NSCLC) cell line-derived xenograft (CDX) models compared to the ADC competitors Trodelvy and DS-1062. The LCB84 treatments were well tolerated, with no changes in body weight compared to control animals, for all dosing groups. LCB84 has robust cross-reactivity against primate Trop-2, which allows rigorous toxicity studies in monkeys. Remarkably, preliminary toxicity studies using cynomolgus monkeys showed that LCB84 is well tolerated, with calculated therapeutic index (TI, MTD/MED) of ~30 for single dosing and ~40 for repeat dosing. In conclusion, LCB84 is highly effective against Trop-2-positive CDX models in mice at doses that are well tolerated in mice and in primate models. Use of this proprietary plasma-stable cancer-selective linker technology and the Hu2G10 anti-Trop-2 monoclonal antibody that targets cancer-activated Trop-2 has led to a greatly improved next generation ADC for the treatment of various Trop-2-positive solid cancers including TNBC, PDAC, NSCLC and gastric cancer. Citation Format: Hyejung Kim, Emanuela Guerra, Eunji Baek, Yeojin Jeong, Hyogeun You, Byeongjun Yu, Taeik Jang, Alberti Saverio, Chul-Woong Chung, Changsik Park. LCB84, a TROP2-targeted ADC, for treatment of solid tumors that express TROP-2 using the hu2G10 tumor-selective anti-TROP2 monoclonal antibody, a proprietary site-directed conjugation technology and plasma-stable tumor-selective linker chemistry [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 328.
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Zhang, Wei, Michel’le Wright, Moeez Rathore, Ali Vaziri-Gohar, Jordan Winter y Rui Wang. "Abstract PO-131: The role of liver endothelium on pancreatic cancer growth". Cancer Research 81, n.º 22_Supplement (15 de noviembre de 2021): PO—131—PO—131. http://dx.doi.org/10.1158/1538-7445.panca21-po-131.
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Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate among major cancers in the United States, and the 5-year survival rate for patients with metastatic PDAC (mPDAC) is only at 3%. Past studies have shown that the paracrine secretion of soluble factors by endothelial cells (ECs) created a unique niche and promoted the survival of cancer cells (cell growth or chemoresistance) in other types of cancer. The liver is the main site of distant metastases in mPDAC, but the influence of the liver EC microenvironment on mPDAC has not been elucidated. In this study, we determined the paracrine effects of liver ECs on the survival of PDAC and identify involved mechanism. Methods: Primary liver ECs were isolated from non-neoplastic liver tissues to mimic the liver EC microenvironment. Conditioned medium (CM) from liver ECs were collected and then applied to PDAC cells, with CM from PDAC as control CM. Effects of CM on PDAC cell proliferation were measured by the MTT assay. Changes in phosphorylation of receptor tyrosine kinases (RTK) between PDAC CM and EC CM treated PADC cells were determined by a Phospho-RTK Array kit and then validated by Western blotting. Involved RKTs were blocked by antibodies for determining their roles in mediating EC effects on PDAC cells. Lastly, A xenograft tumor model was used to establish PDAC tumors and then treated xenograft mice were subcutaneously injected by either PADC CM or EC CM, and tumors growth was monitored and recorded to evaluate the effect of ECs on PADCs. Results: Compared to PDAC CM, EC CM promoted proliferation in 4 different PDAC cells. We found that human epidermal growth factor receptor 3 (HER3 or ERBB3) was only expressed and activated in BxPC-3 cells (HER3+ve), in which the HER3-AKT signaling pathway was activated by EC CM. Furthermore, blocking HER3 activation with a humanized HER3 antibody, seribantumab, completely blocked EC CM-induced AKT activation and cell proliferation. Moreover, depletion of neuregulin (NRG) from EC CM attenuated HER3-AKT activation and indicated that EC-secreted NRG might play a role in promoting PDAC growth. It is interesting that ERK activation was also observed but was not affected by HER3 inhibition. It implied that EGFR signaling pathway might also be involved in EC CM induced PDAC cell growth. Moreover, the combination of cetuximab, trastuzumab and seribantumab yielded the best inhibitory ability on EC CM promoted cell growth as compared to antibody alone or the combination of two of them. Finally, EC CM promoted PDAC tumor growth was also observed in BxPC-3 derived xenograft mouse model. Conclusions: Our results demonstrated that liver EC-secreted factors promoted PDAC growth either in vitro or in vivo, and HER3 was expressed in a subset of PDAC cells and mediated EC-induced proliferation. Moreover, EGFR pathway may also play a role in EC induced cell growth and needs to be addressed in the future study. Our findings suggest a potential of using the combination of HER antibodies/inhibitors for treating patients with HER3+ve mPDACs. Citation Format: Wei Zhang, Michel’le Wright, Moeez Rathore, Ali Vaziri-Gohar, Jordan Winter, Rui Wang. The role of liver endothelium on pancreatic cancer growth [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-131.
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Koch, Elizabeth, Max London, Amy Berkley, Allison Nixon, Sean Phippen, Kerry White, Amanda Hanson, Samuel Cooper, Christopher Harvey y Michael Briskin. "Abstract 388: AI/ML-driven discovery of a novel proteoglycan for precision targeting of ADCs for disruption of stromal barriers and direct anti-tumor activity". Cancer Research 82, n.º 12_Supplement (15 de junio de 2022): 388. http://dx.doi.org/10.1158/1538-7445.am2022-388.
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Abstract Background: While checkpoint inhibitors (CPIs) such as anti-CTLA-4 and anti-PD-1/L1 have demonstrated efficacy in a number of solid tumor indications, those with high stromal presence have been difficult to treat with minimal response observed. We aimed to use a proprietary machine learning/artificial intelligence platform to identify novel stromal targets to relieve this immunosuppressive barrier and increase CPI responsiveness in difficult to treat indications. Methods: Based on bioinformatic analysis using our single cell RNA atlas, we assessed cancer-associated fibroblasts (CAFs)/fibroblastic cells in cancer tissue for identification of novel targets, including proteoglycans. Antibodies were generated by immunization of humanized mice, and lead antibodies were tested for activity in inhibiting cell adhesion and were further characterized for staining of both CAFs as well as tumor cells. ADCs were developed and tested in vitro for selective tumor cell killing. Results: Bioinformatic analysis identified a unique subset of cancer-associated fibroblasts, termed ecmCAFs, which demonstrated selective expression of Collagen Triple Helix Repeat Containing 1 (CTHRC1). This highly-selective expression pattern suggests it may be ideal as a target for alternative modalities, including ADC targeting or specific T cell activation. In addition, we identified that in certain tumor types, such a triple negative breast cancer and pancreatic ductal adenocarcinoma (PDAC), CTHRC1 is also highly expressed by cancer cells within the tumor and shows a more favorable expression profile for ADC targeting when compared to other stromal proteins such as FAP and LRRC15. We have confirmed surface expression and binding of CTHRC1 by our lead antibodies and have observed robust internalization on both human and mouse cancer cell lines. In vitro killing of tumor cells by ADCs and in vivo PD and efficacy will be presented on both ADCs and naked antibodies. Conclusions: We have identified CTHRC1 as a novel proteoglycan expressed by both ecmCAFs and tumor cells that appears to be an ideal target for both direct inhibition of stromal barrier function as well as targeting of cytotoxic payloads as an ADC. CTHRC1 expression is more selective than the classical markers FAP and LRRC15, both of which have been previously developed as ADCs. Citation Format: Elizabeth Koch, Max London, Amy Berkley, Allison Nixon, Sean Phippen, Kerry White, Amanda Hanson, Samuel Cooper, Christopher Harvey, Michael Briskin. AI/ML-driven discovery of a novel proteoglycan for precision targeting of ADCs for disruption of stromal barriers and direct anti-tumor activity [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 388.
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Lewis, Clayton S., Aniruddha Karve, Kateryna Matiash, Timothy Stone, Jingxing Li, Jordon K. Wang, Henri H. Versteeg et al. "A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma". Frontiers in Oncology 11 (29 de julio de 2021). http://dx.doi.org/10.3389/fonc.2021.691685.
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In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC. Previously, we have shown that the growth of PDAC cells is suppressed when they are co-implanted with RabMab1, a rabbit monoclonal antibody specific for human alternatively spliced tissue factor (asTF). Here, we report on humanization of RabMab1, evaluation of its binding characteristics, and assessment of its in vivo properties. hRabMab1 binds asTF with a KD in the picomolar range; suppresses the migration of high-grade Pt45.P1 cells in Boyden chamber assays; has a long half-life in circulation (~ 5 weeks); and significantly slows the growth of pre-formed orthotopic Pt45.P1 tumors in athymic nude mice when administered intravenously. Immunohistochemical analysis of tumor tissue demonstrates the suppression of i) PDAC cell proliferation, ii) macrophage infiltration, and iii) neovascularization, whereas RNAseq analysis of tumor tissue reveals the suppression of pathways that promote cell division and focal adhesion. This is the first proof-of-concept study whereby a novel biologic targeting asTF has been investigated as a systemically administered single agent, with encouraging results. Given that hRabMab1 has a favorable PK profile and is able to suppress the growth of human PDAC cells in vivo, it comprises a promising candidate for further clinical development.
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Baart, Victor M., Labrinus van Manen, Shadhvi S. Bhairosingh, Floris A. Vuijk, Luisa Iamele, Hugo de Jonge, Claudia Scotti et al. "Side-by-Side Comparison of uPAR-Targeting Optical Imaging Antibodies and Antibody Fragments for Fluorescence-Guided Surgery of Solid Tumors". Molecular Imaging and Biology, 12 de octubre de 2021. http://dx.doi.org/10.1007/s11307-021-01657-2.
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Abstract Purpose Radical resection is paramount for curative oncological surgery. Fluorescence-guided surgery (FGS) aids in intraoperative identification of tumor-positive resection margins. This study aims to assess the feasibility of urokinase plasminogen activator receptor (uPAR) targeting antibody fragments for FGS in a direct comparison with their parent IgG in various relevant in vivo models. Procedures Humanized anti-uPAR monoclonal antibody MNPR-101 (uIgG) was proteolytically digested into F(ab’)2 and Fab fragments named uFab2 and uFab. Surface plasmon resonance (SPR) and cell assays were used to determine in vitro binding before and after fluorescent labeling with IRDye800CW. Mice bearing subcutaneous HT-29 human colonic cancer cells were imaged serially for up to 120 h after fluorescent tracer administration. Imaging characteristics and ex vivo organ biodistribution were further compared in orthotopic pancreatic ductal adenocarcinoma (BxPc-3-luc2), head-and-neck squamous cell carcinoma (OSC-19-luc2-GFP), and peritoneal carcinomatosis (HT29-luc2) models using the clinical Artemis fluorescence imaging system. Results Unconjugated and conjugated uIgG, uFab2, and uFab specifically recognized uPAR in the nanomolar range as determined by SPR and cell assays. Subcutaneous tumors were clearly identifiable with tumor-to-background ratios (TBRs) > 2 after 72 h for uIgG-800F and 24 h for uFab2-800F and uFab-800F. For the latter two, mean fluorescence intensities (MFIs) dipped below predetermined threshold after 72 h and 36 h, respectively. Tumors were easily identified in the orthotopic models with uIgG-800F consistently having the highest MFIs and uFab2-800F and uFab-800F having similar values. In biodistribution studies, kidney and liver fluorescence approached tumor fluorescence after uIgG-800F administration and surpassed tumor fluorescence after uFab2-800F or uFab-800F administration, resulting in interference in the abdominal orthotopic mouse models. Conclusions In a side-by-side comparison, FGS with uPAR-targeting antibody fragments compared with the parent IgG resulted in earlier tumor visualization at the expense of peak fluorescence intensity.