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Zhang, Hongpan, Zhihao Yang, Guobo Du, Lu Cao, and BangXian Tan. "CD155-Prognostic and Immunotherapeutic Implications Based on Multiple Analyses of Databases Across 33 Human Cancers." Technology in Cancer Research & Treatment 20 (January 1, 2021): 153303382098008. http://dx.doi.org/10.1177/1533033820980088.
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Growing evidence has suggested that CD155 participates in the regulation of many biological processes ranging cell growth, invasion, and migration from regulation of immune responses in most malignances. However, the impact of prognostic value and CD115-related immune response on the survival in multiple cancers remains incompletely clear. In our study, we assessed the prognostic significance and immune-associated mechanism of CD155 based on data from multiple databases and methods, including UCSC Xena, Oncomine, PrognoScan. We identified that CD155 was commonly upregulated in most human cancers, and High expression of CD155 was closely correlated with unfavorable clinical outcomes in 10/33 of human cancers, while CD155 at low level was responsible for better survival in KICH and PAAD. More intriguingly, CD155 expression had a significant interaction with immune function in several tumors by analyzing Tumor mutational burden and microsatellite in stability, immune score and stromal score. The correlation between immune infiltration and CD155 expression also indicated that CD155 expression positively correlated with CD4+ T cells in Head and Neck squamous cell carcinoma, Lung adenocarcinoma and Colon adenocarcinoma, while had inversely interaction with CD8+ T in Kidney renal clear cell carcinoma and Head and Neck squamous cell carcinoma as well as Tregs in Skin Cutaneous Melanoma, Head and Neck squamous cell carcinoma and Bladder Urothelial Carcinoma. These findings indicate CD155 correlates with cancer immunotherapy function. In conclusions, our observations revealed CD155 might function as immune-associated system in the development of human cancers, and acted as a promising prognostic and therapeutic target against human cancers.
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Yoshikawa, Katsuhiro, Mitsuaki Ishida, Hirotsugu Yanai, Koji Tsuta, Mitsugu Sekimoto, and Tomoharu Sugie. "Immunohistochemical analysis of CD155 expression in triple-negative breast cancer patients." PLOS ONE 16, no. 6 (June 11, 2021): e0253176. http://dx.doi.org/10.1371/journal.pone.0253176.
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Introduction CD155 is an immune checkpoint protein. Its overexpression is an indicator of poor prognosis in some types of cancer. However, the significance of CD155 expression in patients with triple-negative breast cancer, and the relationship between CD155 and programmed death-ligand 1 (PD-L1) expression, have not yet been analyzed in detail. Methods Using immunohistochemical staining and tissue microarrays, we analyzed the expression profiles of CD155 and PD-L1 in 61 patients with triple-negative breast cancer. Relapse-free survival and overall survival rates were compared according to CD155 expression. The correlation between CD155 expression and clinicopathological factors, including PD-L1 expression (using SP142 and 73–10 assays), was also examined. Results CD155 expression was noted in 25 patients (41.0%) in this cohort. CD155 expression did not correlate with pathological stage, histological grade, Ki-67 labeling index, or stromal tumor-infiltrating lymphocytes. Only PD-L1 expression in tumor cells by SP142 assay significantly correlated with CD155 expression (p = 0.035); however, PD-L1 expression in tumor cells by 73–10 assay did not show a correlation (p = 0.115). Using the 73–10 assay, 59% of patients showed CD155 and/or PD-L1 expression in tumor cells. Moreover, using the SP142 assay, 63.3% of patients showed CD155 and/or PD-L1 expression in immune cells. CD155 expression did not correlate with either relapse-free survival or overall survival (p = 0.485 and 0.843, respectively). Conclusions CD155 may be a novel target for antitumor immunotherapy. The results of this study indicate that CD155 may expand the pool of candidates with triple-negative breast cancer who could benefit from antitumor immunotherapy.
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Zhu, Xudong, Rongpu Liang, Tianyun Lan, Dongbing Ding, Shengxin Huang, Jun Shao, Zongheng Zheng, et al. "Tumor-associated macrophage-specific CD155 contributes to M2-phenotype transition, immunosuppression, and tumor progression in colorectal cancer." Journal for ImmunoTherapy of Cancer 10, no. 9 (September 2022): e004219. http://dx.doi.org/10.1136/jitc-2021-004219.
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BackgroundOnco-immunogenic molecule CD155 is overexpressed in various tumor microenvironments (TME) including in colorectal cancer (CRC). Tumor-associated macrophages (TAMs) are the most abundant immune cells in CRC TME and play a vital role in CRC progression and metastasis. Most studies have focused on investigating the role of CRC cell-specific CD155 on CRC progression, while the contribution of TAMs-specific CD155 is still unknown. Here, we sought to investigate the expression pattern of CD155 in CRC TAMs and its role in tumor immunity and progression.MethodsCD155 expression patterns in CRC TAMs and macrophages in paratumor or adjacent normal tissue were analyzed in 50 patients with CRC using flow cytometry and in 141 patients with CRC using immunohistochemistry. The correlation of CD155 expression level in TAMs with M1 and M2 phenotypic transition was analyzed. The role of macrophage-specific CD155 in CRC progression and tumor immune response was investigated in vitro and in vivo. We further analyzed the effect of CRC cells on the regulation of CD155 expression in macrophages.ResultsCRC TAMs from clinical samples showed robustly higher expression of CD155 than macrophages from paratumor and adjacent normal tissues. The CD155 expression level was higher in TAMs of CRC at III/IV stages compared with the I/II stages and was negatively associated with the survival of patients with CRC. CD155+ TAMs showed an M2 phenotype and higher expression of interleukin (IL)-10 and transforming growth factor (TGF)-β. CD155+ macrophages promoted CRC cell migration, invasion, and tumor growth supporting the findings from the clinical tissue analysis. This effect was mainly regulated by TGF-β-induced STAT3 activation-mediated release of matrix metalloproteinases (MMP)2 and MMP9 in CRC cells. CD155–⁄– bone marrow transplantation in wild-type mice, as well as CD155– macrophages treatment, promoted the antitumor immune response in the mice ectopic CRC model. Additionally, CRC cells released IL-4 to trigger CD155 expression in macrophages indicating the regulatory role of CRC cells in the development of CD155+ TAMs.ConclusionsThese findings indicated that CD155+ TAMs are responsible for the M2-phenotype transition, immunosuppression, and tumor progression in CRC. The specific localization of CD155+ TAMs in CRC tissue could turn into a potential therapeutic target for CRC treatment.
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Murakami, Daisuke, Kenji Matsuda, Hiromitsu Iwamoto, Yasuyuki Mitani, Yuki Mizumoto, Yuki Nakamura, Ibu Matsuzaki, et al. "Prognostic value of CD155/TIGIT expression in patients with colorectal cancer." PLOS ONE 17, no. 3 (March 24, 2022): e0265908. http://dx.doi.org/10.1371/journal.pone.0265908.
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Introduction The interaction of CD155 with its ligand, the T cell immunoreceptor with Ig and ITIM domains (TIGIT), is being studied owing to its potential to act as a target in the treatment of various solid tumors. However, the relationship between CD155 and TIGIT in colorectal cancer (CRC) prognosis is not known. We hypothesized that the TIGIT–CD155 pathway suppresses the attack of T cells on tumors, thereby affecting CRC prognosis. Methods We examined the expression of CD155 and TIGIT using immunohistochemical staining in 100 consecutive patients with CRC who underwent complete resection of ≤Stage III tumors at Wakayama Medical University Hospital between January and December 2013. We assessed the correlation between CD155 and TIGIT expressions and prognosis as well as the clinicopathological background of CD155 and TIGIT. Results Patients with high CD155 and TIGIT expressions showed worse prognosis than those with other levels of expression (p = 0.026). In multivariate analysis that also included the existing prognostic markers, high CD155 and TIGIT expressions were identified as independent poor prognostic factors. Conclusions The interaction between CD155 and TIGIT possibly plays an important role in the immunological mechanism of CRC. Therefore, it may be possible to effectively predict the postoperative prognosis of CRC by evaluating the combined expression of CD155 and TIGIT. The study findings suggest that CD155 and TIGIT can predict clinical outcomes, thereby contributing to the personalized care of CRC.
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Yan, Zhang. "Increased expression of CD155 and CD112 on monocytes in septic patients (INC6P.327)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 192.29. http://dx.doi.org/10.4049/jimmunol.194.supp.192.29.
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Abstract The poliovirus receptor CD155 and its family member CD112 (PRR-2 (poliovirus receptor-related family 2), also called nectin-2) are ligands for human and mouse CD226. Human CD112 and CD155 are broadly distributed on epithelial and endothelial cells in many tissues, and overexpressed on certain tumors. Several reports have shown that the interaction between CD155 and CD226 are important for the elimination of target cells by NK and cytotoxic T cells, however, it remains elusive how CD155 and CD112 are regulated in sepsis. In our study, we showed that the expression of CD155 and CD112 on monocytes was significantly upregulated in septic patients which all had a significant reduction in expression of HLA-DR on monocytes, an immunosuppression marker of sepsis, indicating the existence of negative correlation between CD155/122 and HLA-DR. Next studies were undergoing on the mechanisms underlying regulation of the expression of CD155 and CD112 in sepsis and whether signals by CD155/CD112 negatively regulated the expression of HLA-DR.
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Tang, Xiyang, Jie Yang, Anping Shi, Yanlu Xiong, Miaomiao Wen, Zhonglin Luo, Huanhuan Tian, et al. "CD155 Cooperates with PD-1/PD-L1 to Promote Proliferation of Esophageal Squamous Cancer Cells via PI3K/Akt and MAPK Signaling Pathways." Cancers 14, no. 22 (November 15, 2022): 5610. http://dx.doi.org/10.3390/cancers14225610.
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Background: Esophageal cancer is still a leading cause of death among all tumors in males, with unsatisfactory responses to novel immunotherapies such as anti-PD-1 agents. Herein, we explored the role of CD155 in esophageal squamous cell cancer (ESCA) and its underlying molecular mechanisms. Methods: Publicly available datasets were used for differential gene expression and immune infiltration analyses, and their correlation with patient survival. A total of 322 ESCA and 161 paracancer samples were collected and evaluated by performing immunohistochemistry and the H score was obtained by performing semiquantitative analysis. In vitro transfection of ESCA cell lines with lentivirus vectors targeting CD155 was performed to knockdown the protein. These cells were analyzed by conducting RNA sequencing, and the effects of CD155 knockdown on cell cycle and apoptosis were verified with flow cytometry and Western blotting. In addition, in vivo experiments using these engineered cell lines were performed to determine the role of CD155 in tumor formation. A small interfering RNA-mediated knockdown of Nectin3 was used to determine whether it phenocopied the profile of CD155 knockdown. Results: CD155 is highly expressed in ESCA tissues and is positively associated with PD1, PDL1, CD4, IL2RA, and S100A9 expression. Furthermore, CD155 knockdown inhibited ESCA cells’ proliferation by impairing the cell cycle and inducing cell apoptosis. Bioinformatics analysis of the gene expression profile of these engineered cells showed that CD155 mainly contributed to the regulation of PI3K/Akt and MAPK signals. The downregulation of Nectin3 expression phenocopied the profile of CD155 knockdown. Discussion: CD155 may cooperate with PD-1/PD-L1 to support ESCA proliferation in ways other than regulating its underlying immune mechanisms. Indeed, CD155 downregulation can impair ESCA cell pro-cancerous behavior via the inhibition of the PI3K/Akt and MAPK signaling pathways. Moreover, Nectin3 may be a ligand of CD155 and participate in the regulation of ESCA cells’ proliferation. Hence, the inhibition of CD155 may enhance the therapeutic effect of anti-PD-1 immunotherapies in ESCA.
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Li, Yu-Chen, Quan Zhou, Qing-Kun Song, Rui-Bin Wang, Shuzhen Lyu, Xiudong Guan, Yan-Jie Zhao, and Jiang-Ping Wu. "Overexpression of an Immune Checkpoint (CD155) in Breast Cancer Associated with Prognostic Significance and Exhausted Tumor-Infiltrating Lymphocytes: A Cohort Study." Journal of Immunology Research 2020 (January 13, 2020): 1–9. http://dx.doi.org/10.1155/2020/3948928.
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Purpose. The immune checkpoint inhibitor is approved for breast cancer treatment, but the low expression of PD-L1 limits the immunotherapy. CD155 is another immune checkpoint protein in cancers and interacts with ligands to regulate immune microenvironment. This study is aimed at investigating the expression of CD155 and the association with prognosis and pathological features of breast cancer. Methods. 126 patients were recruited this cohort study consecutively, and CD155 expression on tumor cells was detected by immunohistochemistry. The Kaplan-Meier survival curve and Cox hazard regression model were used to estimate the association. Results. 38.1% patients had an overexpression of CD155, and the proportion of tumor cells with CD155 overexpression was 17%, 39%, 37%, and 62% among Luminal A, Luminal B, HER2-positive, and triple negative breast cancer cases, respectively (p<0.05). Patients with CD155 overexpression had the Ki-67 index significantly higher than that of patients with low expression (42% vs. 26%). Though the number of tumor-infiltrating lymphocytes was higher among patients with CD155 overexpression (144/HPF vs. 95/HPF), the number of PD-1+ lymphocytes was significantly higher (52/HPF vs. 25/HPF, p<0.05). Patients of CD155 overexpression had the disease-free and overall survival decreased by 13 months and 9 months, respectively (p<0.05). CD155 overexpression was associated with an increased relapse (HR=13.93, 95% CI 2.82, 68.91) and death risk for breast cancer patients (HR=5.47,1.42,20.99). Conclusions. Overexpression of CD155 was correlated with more proliferative cancer cells and a dysfunctional immune microenvironment. CD155 overexpression introduced a worse relapse-free and overall survival and might be a potential immunotherapy target for breast cancer.
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He, Yongning, Steffen Mueller, Paul R. Chipman, Carol M. Bator, Xiaozhong Peng, Valorie D. Bowman, Suchetana Mukhopadhyay, Eckard Wimmer, Richard J. Kuhn, and Michael G. Rossmann. "Complexes of Poliovirus Serotypes with Their Common Cellular Receptor, CD155." Journal of Virology 77, no. 8 (April 15, 2003): 4827–35. http://dx.doi.org/10.1128/jvi.77.8.4827-4835.2003.
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ABSTRACT Structures of all three poliovirus (PV) serotypes (PV1, PV2, and PV3) complexed with their cellular receptor, PV receptor (PVR or CD155), were determined by cryoelectron microscopy. Both glycosylated and fully deglycosylated CD155 exhibited similar binding sites and orientations in the viral canyon for all three PV serotypes, showing that all three serotypes use a common mechanism for cell entry. Difference maps between the glycosylated and deglycosylated CD155 complexes determined the sites of the carbohydrate moieties that, in turn, helped to verify the position of the receptor relative to the viral surface. The proximity of the CD155 carbohydrate site at Asn105 to the viral surface in the receptor-virus complex suggests that it might interfere with receptor docking, an observation consistent with the properties of mutant CD155. The footprints of CD155 on PV surfaces indicate that the south rim of the canyon dominates the virus-receptor interactions and may correspond to the initial CD155 binding state of the receptor-mediated viral uncoating. In contrast, the interaction of CD155 with the north rim of the canyon, especially the region immediately outside the viral hydrophobic pocket that normally binds a cellular “pocket factor,” may be critical for the release of the pocket factor, decreasing the virus stability and hence initiating uncoating. The large area of the CD155 footprint on the PV surface, in comparison with other picornavirus-receptor interactions, could be a potential limitation on the viability of PV escape mutants from antibody neutralization. Many of these are likely to have lost their ability to bind CD155, resulting in there being only three PV serotypes.
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Chandramohan, Vidyalakshmi, Jeffrey D. Bryant, Hailan Piao, Stephen T. Keir, Eric S. Lipp, Michaela Lefaivre, Kathryn Perkinson, Darell D. Bigner, Matthias Gromeier, and Roger E. McLendon. "Validation of an Immunohistochemistry Assay for Detection of CD155, the Poliovirus Receptor, in Malignant Gliomas." Archives of Pathology & Laboratory Medicine 141, no. 12 (December 1, 2017): 1697–704. http://dx.doi.org/10.5858/arpa.2016-0580-oa.
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Context.— The oncolytic polio-rhinovirus recombinant (PVSRIPO) has demonstrated promise in currently ongoing phase I/II clinical trials against recurrent glioblastoma and was granted breakthrough therapy designation by the Food and Drug Administration/Center for Biologics Evaluation and Research. A reliable clinical assay to document expression of the poliovirus receptor, CD155, in routinely available patient tumor samples is needed for continued clinical development of PVSRIPO oncolytic immunotherapy in primary brain tumors and beyond. Objectives.— To validate a novel anti-CD155 antibody for immunohistochemistry and develop a robust, reliable, and specific protocol for detecting CD155 expression in glioblastoma formalin-fixed, paraffin-embedded (FFPE) tissue samples. To characterize the expression of CD155 in human glioblastoma cells as well as to evaluate the influence of CD155 expression levels on tumor cell susceptibility to PVSRIPO infection and killing. Design.— Immunohistochemical staining on glioblastoma FFPE tissue sections and immunoblot of corresponding frozen tissues were performed. Positive controls were confirmed sites of poliovirus propagation, spinal cord anterior horn, and tonsils; negative controls were vascular smooth muscle in patient samples and FFPE sections from a confirmed CD155-negative Burkitt lymphoma line (Raji). Results.— We succeeded in developing a reliable assay to specifically detect CD155 by immunohistochemistry in glioblastoma FFPE sections. Our data suggest widespread, virtually universal expression of CD155 in glioblastoma cells at levels commensurate with susceptibility to PVSRIPO infection and killing. Conclusions.— Anti-CD155 antibody D3G7H achieves monospecific detection of CD155 in immunoblots of tumor homogenates and immunohistochemistry of tumor FFPE sections. Our assay has utility in defining appropriate use of PVSRIPO in oncolytic immunotherapy against malignant glioma and other cancer histotypes.
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Cho, Monica, Madison Phillips, Longzhen Song, Amy Erbe-Gurel, and Christian M. Capitini. "CD155 axis modulation promotes natural killer cell-mediated graft-versus-tumor effects against osteosarcoma." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 62.06. http://dx.doi.org/10.4049/jimmunol.208.supp.62.06.
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Abstract Patients with relapsed/refractory osteosarcoma (OSA) have a poor prognosis with few treatment options. Immunotherapy with allogeneic natural killer (NK) cells after allogeneic bone marrow transplant (BMT) is an attractive approach to employ a graft-versus-tumor (GVT) effect against OSA. However, NK cells have had limited success against solid tumors in vivo. CD155 is overexpressed on OSA and interacts with DNAM-1, an activating ligand, and TIGIT, an inhibitory ligand, on NK cells. The impact of blocking CD155 after allogeneic BMT is unknown. IL-15-expanded C57BL/6 (B6, H-2b) and BALB/c (H-2d) murine NK cells were co-cultured with K7M2 murine OSA (H-2d) after CD155 and CD155 ligand blockade, and analyzed by flow cytometry and cytotoxicity assays. BALB/c mice were also transplanted with T cell depleted allogeneic B6 or syngeneic BALB/c bone marrow, challenged with K7M2 and treated with IL-15-expanded NK cells and CD155 blockade. Allogeneic NK cells showed increased degranulation, interferon-gamma production and cytotoxicity against K7M2 OSA in vitro compared to syngeneic NK cells. NK cell activation and cytotoxicity were further enhanced by CD155 and TIGIT blockade, but decreased with DNAM-1 blockade. In vivo, allogeneic NK cell infusion and anti-CD155 treatment decreased tumor growth and increased survival compared to syngeneic NK cell treatment, without induction of graft-versus-host-disease. CD155 blockade augments NK cell activation, cytotoxicity and GVT effects against OSA without toxicity, suggesting TIGIT is the dominant CD155 checkpoint during allogeneic BMT. CD155 blockade with allogeneic NK cell therapy after BMT may be an effective combination immunotherapy platform for treating relapsed/refractory OSA. Supported by NIH grants (T32 CA009135, R01 CA215461)
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Tzaridis, Theophilos, Tanja Eisemann, Augusto F. Andrade, Jennifer L. Hope, Megan M. Romero, Oren J. Becher, Nada Jabado, Linda M. Bradley, and Robert J. Wechsler-Reya. "DIPG-17. CD155 regulates cell growth and immune evasion in diffuse intrinsic pontine glioma." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i21. http://dx.doi.org/10.1093/neuonc/noac079.074.
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Abstract There is an unmet need for more effective treatment strategies for diffuse intrinsic pontine glioma (DIPG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach to treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DIPG patients. In this study, we analysed the expression of immune checkpoint molecules on the surface of human and murine DIPG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of PD-L1, PD-L2, Galectin-9, CEACAM-1, CD86, CD252 and CD137. These findings were confirmed in primary patient samples from pediatric brain tumours, including high-grade gliomas, medulloblastomas and ependymomas. To test whether CD155 inhibition increases susceptibility to CD8+ T cell killing in vitro, we cultured DIPG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. Addition of CD155 blocking antibodies to these cultures increased expression of T cell activation markers (CD25, CD44 and CD69) as well as T cell-mediated tumour killing, supporting the notion that CD155 can function as an immune checkpoint in DIPG. In addition to its effects on T cells, CD155 also exerted direct effects on tumour cells: treatment with anti-CD155 antibodies led to impaired cell viability, and shRNA-mediated knockdown of CD155 resulted in reduced cell proliferation in vitro. Strikingly, knockdown of CD155 also led to reduced growth of DIPG cells in vivo, and mice transplanted with the CD155-deficient cells had a clear survival benefit compared to mice transplanted with wild type cells. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumor growth in DIPG, and suggest that targeting CD155 could be a valuable therapeutic strategy for this devastating disease.
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Mantovani, Stefania, Stefania Varchetta, Dalila Mele, Roberta Maiello, Matteo Donadon, Cristiana Soldani, Barbara Franceschini, et al. "Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells." Cancers 14, no. 16 (August 22, 2022): 4060. http://dx.doi.org/10.3390/cancers14164060.
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Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC. Methods: Soluble CD155 was measured by ELISA. CD155 expression was sought in HCC cells by immunohistochemistry, qPCR, and flow cytometry. DNAM-1 modulation in NK cells was evaluated in transwell experiments and by a siRNA-mediated knockdown. NK cell functions were examined by direct DNAM-1 triggering. Results: sCD155 was increased in sera from HCC patients and correlated with the parameters of an advanced disease. The expression of CD155 in HCC showed a positive trend toward better overall survival. DNAM-1 downmodulation was induced by CD155-expressing HCC cells, in agreement with lower DNAM-1 expressions in tumor-infiltrating NK (NK-TIL) cells. DNAM-1-mediated cytotoxicity was defective both in circulating NK cells and in NK-TIL of HCC patients. Conclusions: We provide evidence of alterations in the DNAM-1/CD155 axis in HCC, suggesting a possible mechanism of tumor resistance to innate immune surveillance.
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Molfetta, Rosa, Beatrice Zitti, Mario Lecce, Nadia Domenica Milito, Helena Stabile, Cinzia Fionda, Marco Cippitelli, Angela Gismondi, Angela Santoni, and Rossella Paolini. "CD155: A Multi-Functional Molecule in Tumor Progression." International Journal of Molecular Sciences 21, no. 3 (January 30, 2020): 922. http://dx.doi.org/10.3390/ijms21030922.
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CD155 is an adhesion molecule belonging to the Nectin/Nectin-like family often overexpressed on tumor cells and involved in many different processes such as cell adhesion, migration and proliferation. In contrast to these pro-tumorigenic functions, CD155 is also a ligand for the activating receptor DNAM-1 expressed on cytotoxic lymphocytes including Natural Killer (NK) cells and involved in anti-tumor immune response. However, during tumor progression inhibitory receptors for CD155 are up-regulated on the surface of effector cells, contributing to an impairment of their cytotoxic capacity. In this review we will focus on the roles of CD155 as a ligand for the activating receptor DNAM-1 regulating immune surveillance against cancer and as pro-oncogenic molecule favoring tumor proliferation, invasion and immune evasion. A deeper understanding of the multiple roles played by CD155 in cancer development contributes to improving anti-tumor strategies aimed to potentiate immune response against cancer.
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Gosselin, Anne-Sophie, Yannick Simonin, Florence Guivel-Benhassine, Vincent Rincheval, Jean-Luc Vayssière, Bernard Mignotte, Florence Colbère-Garapin, Thérèse Couderc, and Bruno Blondel. "Poliovirus-Induced Apoptosis Is Reduced in Cells Expressing a Mutant CD155 Selected during Persistent Poliovirus Infection in Neuroblastoma Cells." Journal of Virology 77, no. 1 (January 1, 2003): 790–98. http://dx.doi.org/10.1128/jvi.77.1.790-798.2003.
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ABSTRACT Poliovirus (PV) can establish persistent infections in human neuroblastoma IMR-32 cells. We previously showed that during persistent infection, specific mutations were selected in the first extracellular domain of the PV receptor (CD155) of these cells (N. Pavio, T. Couderc, S. Girard, J. Y. Sgro, B. Blondel, and F. Colbère-Garapin, Virology 274:331-342, 2000). These mutations included the Ala 67 → Thr substitution, corresponding to a previously described allelic form of the PV receptor. The mutated CD155Thr67 and the nonmutated IMR-32 CD155 (CD155IMR) were expressed independently in murine LM cells lacking the CD155 gene. Following infection of the cells with PV, we analyzed the death of cells expressing these two forms of CD155. Levels of DNA fragmentation, caspase activity, and cytochrome c release were lower in LM-CD155Thr67 cells than in LM-CD155IMR cells. Thus, the level of apoptosis was lower in cells expressing mutated CD155 selected during persistent PV infection in IMR-32 than in cells expressing the wild-type receptor.
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Cho, Monica, Madison Phillips, Longzhen Song, Amy Erbe, and Christian Capitini. "147 CD155 blockade boosts alloreactive natural killer cell antitumor effects against osteosarcoma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A160. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0147.
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BackgroundPediatric patients with relapsed and refractory osteosarcoma have poor prognoses with few treatment options. Allogeneic bone marrow transplant (BMT) has not yet shown a graft-versus-tumor (GVT) effect for osteosarcoma. Natural killer (NK) cells demonstrate antitumor activity against osteosarcoma, but adoptively transferred NK cells have limited proliferation, cytotoxicity, and persistence in vivo. To enhance an NK-specific GVT effect, we propose blocking the poliovirus receptor CD155 checkpoint molecule, which is overexpressed on osteosarcoma and can engage both activating and inhibitory receptors on NK cells. The impact of CD155 blockade on GVT and graft-versus-host-disease (GVHD) is unknown.MethodsNK cells from C57BL/6 (B6) mice were expanded with recombinant IL-15/IL-15R and analyzed by flow cytometry. Cytotoxicity assays were performed with IL-15 expanded B6 NK cells and mKate2-expressing K7M2 murine osteosarcoma at a 1:1 ratio with blockade of CD155 and CD155 ligands. To test efficacy of NK cell infusion and CD155 blockade after allogeneic BMT, BALB/c mice were lethally irradiated, transplanted with allogeneic B6 bone marrow, and challenged with luciferase-expressing K7M2 on day 0. At day 7, mice received IL-15 expanded B6 NK cells intravenously with either anti-IgG control or anti-CD155 antibody intraperitoneally and IL-2 subcutaneously on days 7 and 11. Mice were monitored for tumor growth by bioluminescence, and toxicity by GVHD using weight loss and clinical scores.ResultsCompared to unexpanded murine NK cells, IL-15 expanded NK cells (n = 6) show increased expression of NKG2D (65.33 ± 10.77% NKG2D+, p = 0.0077; 1030 ± 177.0 MFI, p = 0.0101) and an increased ratio of the CD155 activating (CD226) to inhibitory (TIGIT) ligand expression (11.71 ± 4.121, p = 0.0362). In cytotoxicity assays with IL-15 expanded allogeneic murine NK cells (n = 3 replicates), CD155 blockade enhances K7M2 osteosarcoma lysis (60.62 ± 3.19%, p = 0.0189) compared to IgG control (29.01 ± 7.66%). CD226 blockade decreased tumor killing (10.62 ± 8.51%, p = 0.0053) compared to CD155 blockade. In vivo allogeneic murine NK cell infusion and anti-CD155 antibody treatment after allogeneic BMT decreased tumor area under the curve by 44.3% compared to IgG control, without exacerbating GVHD.ConclusionsThese findings demonstrate that blockade of CD155 enhances an allogeneic NK cell-specific GVT effect for osteosarcoma treatment without exacerbating GVHD. CD155 blockade has the potential to improve usage of allogeneic BMT and NK cell adoptive immunotherapy as a combination treatment for osteosarcoma, and perhaps other pediatric sarcomas.AcknowledgementsThis work was supported by grants from the National Institute of General Medical Sciences/NIH T32 GM008692 and Training in Cancer Biology Training Grant NIH T32 CA009135 (to MMC), St. Baldrick’s Stand up to Cancer (SU2C) Pediatric Dream Team Translational Research Grant SU2C-AACR-DT-27-17, NCI/NIH R01 CA215461, American Cancer Society Research Scholar Grant RSG- 18-104-01-LIB, and the Midwest Athletes Against Childhood Cancer (MACC) Fund (to CMC). SU2C is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. The contents of this article do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.
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Nemčovičová, Ivana, and Dirk M. Zajonc. "The structure of cytomegalovirus immune modulator UL141 highlights structural Ig-fold versatility for receptor binding." Acta Crystallographica Section D Biological Crystallography 70, no. 3 (February 22, 2014): 851–62. http://dx.doi.org/10.1107/s1399004713033750.
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Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid immune recognition and to allow long-term persistence in the host,Human cytomegalovirus(HCMV) has evolved a number of genes to evade or inhibit immune effector pathways. In particular, UL141 can inhibit cell-surface expression of both the NK cell-activating ligand CD155 as well as the TRAIL death receptors (TRAIL-R1 and TRAIL-R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed analysis of its head-to-tail dimerization interface. A `dimerization-deficient' mutant of UL141 (ddUL141) was further designed, which retained the ability to bind to TRAIL-R2 or CD155 while losing the ability to cross-link two receptor monomers. Structural comparison of unliganded UL141 with UL141 bound to TRAIL-R2 further identified a mobile loop that makes intimate contacts with TRAIL-R2 upon receptor engagement. Superposition of the Ig-like domain of UL141 on the CD155 ligand T-cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig-like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar `lock-and-key' interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)X6G `lock' motif for CD155 binding as well as conservation of the TRAIL-R2 binding patches, suggesting that these host–receptor interactions are evolutionary conserved.
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Fittje, Pia, Angelique Hœlzemer, Wilfredo F. Garcia-Beltran, Sarah Vollmers, Annika Niehrs, Kerri Hagemann, Glòria Martrus, et al. "HIV-1 Nef-mediated downregulation of CD155 results in viral restriction by KIR2DL5+ NK cells." PLOS Pathogens 18, no. 6 (June 24, 2022): e1010572. http://dx.doi.org/10.1371/journal.ppat.1010572.
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Antiviral NK cell activity is regulated through the interaction of activating and inhibitory NK cell receptors with their ligands on infected cells. HLA class I molecules serve as ligands for most killer cell immunoglobulin-like receptors (KIRs), but no HLA class I ligands for the inhibitory NK cell receptor KIR2DL5 have been identified to date. Using a NK cell receptor/ligand screening approach, we observed no strong binding of KIR2DL5 to HLA class I or class II molecules, but confirmed that KIR2DL5 binds to the poliovirus receptor (PVR, CD155). Functional studies using primary human NK cells revealed a significantly decreased degranulation of KIR2DL5+ NK cells in response to CD155-expressing target cells. We subsequently investigated the role of KIR2DL5/CD155 interactions in HIV-1 infection, and showed that multiple HIV-1 strains significantly decreased CD155 expression levels on HIV-1-infected primary human CD4+ T cells via a Nef-dependent mechanism. Co-culture of NK cells with HIV-1-infected CD4+ T cells revealed enhanced anti-viral activity of KIR2DL5+ NK cells against wild-type versus Nef-deficient viruses, indicating that HIV-1-mediated downregulation of CD155 renders infected cells more susceptible to recognition by KIR2DL5+ NK cells. These data show that CD155 suppresses the antiviral activity of KIR2DL5+ NK cells and is downmodulated by HIV-1 Nef protein as potential trade-off counteracting activating NK cell ligands, demonstrating the ability of NK cells to counteract immune escape mechanisms employed by HIV-1.
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Khan, Shaukat, Hidemi Toyoda, Melissa Linehan, Akiko Iwasaki, Akio Nomoto, Günter Bernhardt, Jeronimo Cello, and Eckard Wimmer. "Poliomyelitis in transgenic mice expressing CD155 under the control of the Tage4 promoter after oral and parenteral poliovirus inoculation." Journal of General Virology 95, no. 8 (August 1, 2014): 1668–76. http://dx.doi.org/10.1099/vir.0.064535-0.
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An important step in poliovirus (PV) infection by the oral route in humans is replication of the virus in lymphatic tissues of the gastrointestinal (GI) tract, thought to be mainly in the Peyer’s patches of the small intestine. No immunocompetent transgenic (tg) mice that express human PV receptor (CD155) under the control of different promoters can be infected orally. The mouse orthologue of human CD155 is Tage4, a protein expressed at the surface of enterocytes and in the Peyer’s patches. We describe here the generation of a tg mouse model in which the Tage4 promoter was used to drive expression of the human PV receptor-coding region (Tage4-CD155tg mice). In this model, CD155 expression was observed by immunostaining in different regions in the Peyer’s patches but not in their germinal centres. Although a similar pattern of staining was observed between 3- and 6-week-old Tage4-CD155tg mice, poliomyelitis was only seen in the younger mice after PV infection by the oral route. When compared with TgPVR21 mice that expressed CD155 driven by its human promoter, 3-week-old Tage4-CD155tg mice were more susceptible to gut infection and paralysis following feeding with PV. Also, Tage4-CD155tg mice exhibited higher susceptibility to poliomyelitis after parenteral inoculation of PV. Remarkably, the LD50 after intracerebral inoculation of PV was similar in both CD155 tg mouse strains. The CD155 tg mouse model reported here, although moderately susceptible to oral infection, may be suitable to study mechanisms of PV replication in the gastrointestinal tract and to dissect important aspects of PV neuroinvasiveness.
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Chen, Lihua, JiuYu Gong, Rongrong Liu, Liang Fang, Ran Zhuang, Yun Zhang, and Boquan Jin. "The unfolded protein response induces the resistance of hepatoma cells to NK cells’ cytotoxicity (178.13)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 178.13. http://dx.doi.org/10.4049/jimmunol.188.supp.178.13.
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Abstract NK cells, as a critical components of anti-tumor immunity, recognize and kill malignant cells through the specific NK cell activating receptors. CD226 and NKG2D are known as important NK cell activating receptors whose ligands are CD112, CD155 and MICA/B, respectively. It has been proven that CD112, CD155 and MICA/B highly express on a series of tumors and directly affect the cytotoxicity of NK cells to the malignant cells. Here we showed that the unfolded protein response induced by tunicamycin could decrease the expression levels of CD112, CD155 and MICA/B on hepatoma cells via the ATF6 and IRE1 pathway and induce the resistance of hepatoma cells to NK cells’ cytotoxicity. Furthermore, the IRE1 pathway increased the expression of the ER associated degradation (ERAD) related molecule HRD1 and facilitated the degradation of CD112, CD155 and MICA/B. Moreover, we demonstrated that the expression levels of CD112, CD155 and MICA/B in hepatoma tissues were inversely correlated with the expression level of GRP78 and the TMN grade of hepatocellular carcinoma in vivo. The results suggest that the production of HRD1 is up-regulated to facilitate the hepatoma cells escape from the NK cells’ cytotoxicity by degrading the ligands expression of the NK cells’ activating receptors.
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Baury, Béatrice, Damien Masson, Brian M. McDermott, Anne Jarry, Hervé M. Blottière, Philippe Blanchardie, Christian L. Laboisse, Patrick Lustenberger, Vincent R. Racaniello, and Marc G. Denis. "Identification of secreted CD155 isoforms." Biochemical and Biophysical Research Communications 309, no. 1 (September 2003): 175–82. http://dx.doi.org/10.1016/s0006-291x(03)01560-2.
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Freistadt, MS, and KE Eberle. "Hematopoietic cells from CD155-transgenic mice express CD155 and support poliovirus replication ex vivo." Microbial Pathogenesis 29, no. 4 (October 2000): 203–12. http://dx.doi.org/10.1006/mpat.2000.0386.
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Chen, Lihua, Jiuyu Gong, Liang Fang, and Boquan Jin. "Attenuated NK cell killing to hepatoma cells increases the mortality via decreased expression levels of MICA, CD112 and CD155 during UPR (P2023)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 53.12. http://dx.doi.org/10.4049/jimmunol.190.supp.53.12.
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Abstract Natural killer (NK) cells play important roles in anti-tumor immunity. Here, we demonstrate that the unfolded protein response (UPR) attenuated the sensitivity of hepatoma cells to NK cell cytotoxic activity by decreasing the expression levels of MHC class I-related chain A/B (MICA/B), CD112 and CD155 in human hepatocellular carcinoma (HCC) cells. The decreased expression levels of MICA/B, CD112 and CD155 were due to the involvement of the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1α (IRE1α) pathways. In addition, the IRE1α pathway contributed to the increased expression levels of the ER-associated degradation (ERAD)-related molecule HRD1 and facilitated the degradation of MICA/B, CD112 and CD155. Moreover, we found that low levels of MICA/B, CD112 and CD155 expression were significantly associated with poor prognosis in patients with HCC. Thus, our results provide molecular, cellular and clinical evidence demonstrating a novel NK cell-associated immune evasion mechanism, and indicate that targeting this immune evasion pathway may be meaningful in treating patients with HCC.
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Szereday, Laszlo, David U. Nagy, Beata Csiszar, Dora Kevey, Timoteus Feik, and Matyas Meggyes. "Examination of the TIGIT, CD226, CD112, and CD155 Immune Checkpoint Molecules in Peripheral Blood Mononuclear Cells in Women Diagnosed with Early-Onset Preeclampsia." Biomedicines 9, no. 11 (November 3, 2021): 1608. http://dx.doi.org/10.3390/biomedicines9111608.
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Early-onset preeclampsia is a common obstetrical disease with a potential genetic background and is characterized by the predominance of Th1 immune response. However, although many studies investigated the immunological environment in preeclamptic patients, no information is available about the potential role of the TIGIT/CD226/CD112/CD155 immune checkpoint pathway. A total of 37 pregnant women diagnosed with early-onset preeclampsia and 36 control women with appropriately matched gestational age were enrolled in this study. From venous blood, mononuclear cells were isolated and stored in the freezer. Using multicolor flow cytometry T-, NK cell and monocyte subpopulations were determined. After characterization of the immune cell subsets, TIGIT, CD226, CD112, and CD155 surface expression and intracellular granzyme B content were determined by flow cytometer. Significantly decreased CD226 expression and increased CD112 and CD155 surface expression were detected in almost all investigated T-cell, NK cell, and monocyte subpopulations in women diagnosed with preeclampsia compared to the healthy group. Furthermore, reduced TIGIT and granzyme B expression were measured only in preeclamptic CD8+ T cells compared to healthy pregnant women. A decreased level of the activatory receptor CD226 in effector lymphocytes accompanied with an elevated surface presence of the CD112 and CD155 ligands in monocytes could promote the TIGIT/CD112 and/or TIGIT/CD155 ligation, which mediates inhibitory signals. We assume that the inhibition of the immune response via this immune checkpoint pathway might contribute to compensate for the Th1 predominance during early-onset preeclampsia.
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Prod'homme, Virginie, Daniel M. Sugrue, Richard J. Stanton, Akio Nomoto, James Davies, Carole R. Rickards, Daniel Cochrane, Melanie Moore, Gavin W. G. Wilkinson, and Peter Tomasec. "Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112." Journal of General Virology 91, no. 8 (August 1, 2010): 2034–39. http://dx.doi.org/10.1099/vir.0.021931-0.
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Human cytomegalovirus (HCMV) UL141 induces protection against natural killer cell-mediated cytolysis by downregulating cell surface expression of CD155 (nectin-like molecule 5; poliovirus receptor), a ligand for the activating receptor DNAM-1 (CD226). However, DNAM-1 is also recognized to bind a second ligand, CD112 (nectin-2). We now show that HCMV targets CD112 for proteasome-mediated degradation by 48 h post-infection, thus removing both activating ligands for DNAM-1 from the cell surface during productive infection. Significantly, cell surface expression of both CD112 and CD155 was restored when UL141 was deleted from the HCMV genome. While gpUL141 alone is sufficient to mediate retention of CD155 in the endoplasmic reticulum, UL141 requires assistance from additional HCMV-encoded functions to suppress expression of CD112.
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Kawashima, Shusuke, Takashi Inozume, Masahito Kawazu, Toshihide Ueno, Joji Nagasaki, Etsuko Tanji, Akiko Honobe, et al. "TIGIT/CD155 axis mediates resistance to immunotherapy in patients with melanoma with the inflamed tumor microenvironment." Journal for ImmunoTherapy of Cancer 9, no. 11 (November 2021): e003134. http://dx.doi.org/10.1136/jitc-2021-003134.
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BackgroundPatients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples.MethodsWe established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort.ResultsTwo patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed TME, including both primary and acquired resistance.ConclusionsThe TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.
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Wang, Han, Jianxun Qi, Shuijun Zhang, Yan Li, Shuguang Tan, and George F. Gao. "Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5." Proceedings of the National Academy of Sciences 116, no. 3 (December 27, 2018): 988–96. http://dx.doi.org/10.1073/pnas.1815716116.
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Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.
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Levin, Steven D., Cameron S. Brandt, Edward D. Howard, Janet Johnston, Eric Chadwick, Angela Hammond, David W. Taft, et al. "Identification and Characterization of Vstm3 as an inhibitory member of the CD28 family (90.31)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 90.31. http://dx.doi.org/10.4049/jimmunol.182.supp.90.31.
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Abstract Members of the B7-CD28 family play critical roles in the response of T cells. We have identified the transmembrane protein Vstm3 as a member of the CD28 family based on gene structure. It has two immunoreceptor tyrosine inhibitory motifs in its cytoplasmic domain and is expressed on NK cells and a subset of T cells. Antibodies against VSTM3 antagonize multiple aspects of T cell activation including proliferation and cytokine production indicating it plays an inhibitory role in T cell activation. We have also identified two counter-structures for this protein, the previously identified proteins CD155 and CD112, which are expressed on activated antigen presenting cells. CD155 and CD112 also bind to the activating receptor CD226 and hence this extended family of interacting proteins forms a network of molecules similar to the well characterized CD28-CTLA4-CD80-CD86 network. A soluble form of Vstm3 binds to CD155 and CD112 and disrupts their ability to trigger an activating response through CD226, and hence antagonizes immune responses in vitro and in vivo. On the other hand, an antibody that specifically blocks Vstm3 interaction with CD155 and CD112 tends to enhance T cell responses in vitro and in vivo. Finally, mice that lack Vstm3 are more sensitive to the development of autoimmune diseases. Our data indicate that this novel member of the CD28 family negatively regulates T cell responses.
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Lupo, Kyle, and Sandro Matosevic. "130 Engineered natural killer cells reactively block TIGIT and CD73 in the GBM microenvironment." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A139. http://dx.doi.org/10.1136/jitc-2021-sitc2021.130.
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BackgroundNatural killer (NK) cells have emerged as promising effectors to target GBM and other solid tumors through genetic modifications and ex vivo manipulation. However, immunosuppressive conditions within the tumor microenvironment (TME) and interactions between NK cell activating and inhibitory receptors further complicate NK cell-based treatments. In particular, the T cell immunoreceptor with Ig and ITIM domains (TIGIT) is expressed on NK cells and interacts with CD155 to induce immunosuppression of NK cell cytolytic functions.1 2 Although CD155 also binds with activating receptors DNAM-1 and CD96 on NK cells, spurring NK cell activity, TIGIT has predominantly been reported as having an inhibitory effect on NK cells.3–5 Further, tumor cells release of high levels of ATP extracellularly. While intracellular ATP is necessary for cell metabolism, extracellular ATP is converted into adenosine (ADO) by ectonucleotidases CD39 and CD73, both overexpressed on GBM and other solid tumors.6 Extracellular ADO induces immunometabolic suppression of NK cells through binding with A2A adenosine receptors (A2ARs) on NK cells, suppressing cytokine secretion, proliferation, and other functional activities.7–9 We found that TIGIT and CD73 are effective combination targets in GBM for both primary and iPSC-derived NK cells.MethodsIn order to effectively target immunometabolic reprogramming induced by CD73-produced adenosine and the immunosuppressive TIGIT-CD155 axis, we have engineered NK cells to concomitantly target CD155 and CD73-induced immunosuppression on GBM using a tumor-responsive genetic construct based on the synNotch signaling system. The construct is capable of blocking the immunosuppressive CD155/TIGIT interaction, and, upon binding, release a CD73-blocking scFv to inhibit the accumulation of extracellular ADO and mitigate immunosuppression of NK cells. Such localized response enhances specificity and reduces off-target effects of NK-based targeting.ResultsPrimary NK cells and iPSC-derived NK cells were successfully engineered to express the synthetic TIGIT-synNotch construct, measured through expression of TIGIT. To evaluate the functionality of engineered NK cells against GBM targets, we tested the cytotoxicity of our engineered NK cells against a primary, patient-derived GBM cell line, GBM43. Overall, cytolytic function of engineered NK cells against GBM was significantly higher than that of non-engineered NK cells, with or without CD73 (10 ug/mL) and TIGIT (50 ug/mL) antibodies, for E:T ratios of 5:1 and 10:1, demonstrating the functional efficacy of our genetic construct.ConclusionsOverall, we have shown that co-targeting CD155 and CD73 in a localized, responsive manner can dampen immunosuppression and significantly enhance the killing potential of engineered NK cells against aggressive patient-derived GBM tumors.ReferencesZhang B, et al. Immunoreceptor TIGIT inhibits the cytotoxicity of human cytokine-induced killer cells by interacting with CD155. Cancer Immunol Immunother 2016;65:305–314.Lupo KB & Matosevic S. CD155 immunoregulation as a target for natural killer cell immunotherapy in glioblastoma. J Hematol Oncol 2020;13:76.Hung AL, et al. TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM. OncoImmunology 2018; e1466769. doi:10.1080/2162402X.2018.1466769.Mahnke K & Enk, AH. TIGIT-CD155 Interactions in Melanoma: A Novel Co-Inhibitory Pathway with Potential for Clinical Intervention. Journal of Investigative Dermatology 2016; 136, 9–11.Stanietsky N, et al. Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR: Innate immunity. Eur J Immunol 2013; 43:2138–2150.Chambers AM, et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front Immunol 2018;9:2533.Chambers AM, Lupo KB & Matosevic S. Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells. Front Immunol 2018;9:2517.Chambers AM. et al. Adenosinergic Signaling Alters Natural Killer Cell Functional Responses. Front Immunol 2018;9:2533.Wang J, Lupo KB, Chambers AM & Matosevic S. Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J Immunotherapy Cancer 2018;6:136.Ethics ApprovalPrimary human NK cells were obtained from healthy adult donors approved under Purdue University’s Institutional Review Board (IRB) (IRB-approved protocol #1804020540). Donors gave written informed consent prior to taking part in the study.
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Weiss, Tobias, Hanna Meister, Michael Weller, Charles Sentman, and Patrick Roth. "IMMU-17. TARGETING GLIOBLASTOMA WITH DNAM-1-BASED CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS." Neuro-Oncology 21, Supplement_6 (November 2019): vi122. http://dx.doi.org/10.1093/neuonc/noz175.510.
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Abstract BACKGROUND Genetically engineered T cells that express a chimeric antigen receptor (CAR) have shown powerful anti-tumor activity in extracranial malignancies. This concept is now also being explored against glioblastoma. However, many single target antigens used for CAR cell therapy are non-homogeneously expressed. We assessed the therapeutic potential of CAR T cells targeting 2 antigens which are homogeneously expressed by glioma cells which reduces the probability of tumor immune escape due to antigen loss. METHODS We analyzed the expression of CD112 and CD155, which are ligands to the activating immune cell receptor DNAX Accessory Molecule-1 (DNAM-1), in a panel of mouse and human glioma cell lines as well as in human glioblastoma samples and generated glioma cells with a CD112 or CD155 knock-out. To exploit the specific binding properties of DNAM-1, we generated first or second-generation CAR T cells that use DNAM-1 as an antigen-binding domain and investigated their anti-tumor activity in vitro and in vivo using syngeneic orthotopic mouse glioma models. RESULTS CD112 and CD155 are homogeneously expressed in mouse and human glioma cell lines as well as human glioblastoma tissue specimens. CRISPR/Cas9-mediated knock-out of CD112 or CD155 affected the migration of glioma cells, but had no impact on the proliferation or susceptibility to irradiation or temozolomide. DNAM-1-based CAR T cells exerted high cytolytic activity and secretion of various effector cytokines in vitro. Upon intravenous administration, DNAM-1-based CAR T cells did not exert significant toxicity, homed to the tumor site in the brain and prolonged the survival of orthotopic glioma-bearing mice with durable anti-tumor responses in a fraction of mice. CONCLUSION CD112 and CD155 represent attractive targets for glioma immunotherapy using genetically engineered immune cells. Based on the data obtained from our preclincal assessment of DNAM-1-based CAR T cells, this immunotherapeutic strategy might also be explored in human glioma patients.
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Merrill, Melinda K., Guenter Bernhardt, John H. Sampson, Carol J. Wikstrand, Darell D. Bigner, and Matthias Gromeier. "Poliovirus receptor CD155-targeted oncolysis of glioma." Neuro-Oncology 6, no. 3 (July 1, 2004): 208–17. http://dx.doi.org/10.1215/s1152851703000577.
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Wang, Yan, Ying-Li Luo, Yi-Fang Chen, Zi-Dong Lu, Yue Wang, Anna Czarna, Song Shen, Cong-Fei Xu, and Jun Wang. "Dually regulating the proliferation and the immune microenvironment of melanoma via nanoparticle-delivered siRNA targeting onco-immunologic CD155." Biomaterials Science 8, no. 23 (2020): 6683–94. http://dx.doi.org/10.1039/d0bm01420f.
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Liu, Tian, Dongliang Zhang, Yuan Zhang, Xiangsheng Xu, Bo Zhou, Liang Fang, Yun Zhang, et al. "Blocking CD226 Promotes Allogeneic Transplant Immune Tolerance and Improves Skin Graft Survival by Increasing the Frequency of Regulatory T Cells in a Murine Model." Cellular Physiology and Biochemistry 45, no. 6 (2018): 2338–50. http://dx.doi.org/10.1159/000488182.
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Background/Aims: Regulatory T cells (Tregs) play key roles in maintaining peripheral tolerance and preventing autoimmune disease. Treg modulation could be helpful in treating malignancies, autoimmune disease, and allergies, as well as to facilitate organ transplantation. Signals transduced by co-stimulatory molecules are essential for Treg differentiation, homeostasis, and function. One well-known active receptor, CD226, also known as DNAM-1 or PTA1, is an adhesion molecule that interacts primarily with CD155 and is involved in Treg differentiation and immune tolerance to transplanted tissue. Methods: Anti-CD226 monoclonal antibody (mAb) and truncated recombinant CD226 proteins were employed to manipulate the CD226 signal. Various T cell markers on freshly isolated splenocytes and T lymphocytes were characterized by flow cytometry Cell proliferation was measured by carboxyfluorescein succinimidyl ester dye, mRNA transcripts by q-RT PCR, and protein expression by western blotting. A BALB/c-to-C57BL/6 skin allograft model was used to determine the effects of CD226 blocking treatment. Results: We observed that both intact extracellular domains of CD226 were necessary for functional interaction of the receptor with its ligand CD155, even though one domain was shown to bind CD155 with lower affinity in a solid binding assay. Importantly, CD226 mAb promoted Treg expansion in a mixed lymphocyte culture and inhibited the cytotoxicity of effector cells. In allogeneic skin transplant mice, administering CD226 mAb reduced inflammation and prolonged allogeneic graft survival, with an increase in the frequency of Tregs. Conclusions: Our results reveal the mechanism underlying CD226-CD155 interactions and indicate that CD226 signals can be manipulated to promote Treg expansion. Moreover, we provide new evidence that suggests the therapeutic potential of anti-CD226 with allogeneic transplantation.
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Nahas, Myrna, Dina Stroopinsky, Marzia Capelletti, Jacalyn Rosenblatt, Shira Orr, Haider Ghiasuddin, Adam Morin, Jessica Liegel, Donald Kufe, and David E. Avigan. "CD155-Tigit Pathway Modulation in Dendritic Cell/Acute Myeloid Leukemia Fusion Vaccine Model." Blood 134, Supplement_1 (November 13, 2019): 1386. http://dx.doi.org/10.1182/blood-2019-122438.
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Background: We developed a vaccine consisting of primary AML cells fused with autologous dendritic cells (DC) such that a broad array of antigens are presented in the context of DC-mediated costimulation, thereby expanding the anti-AML T cell repertoire. The reestablishment of tumor tolerance by the microenvironment (TME) can limit vaccine efficacy and reversal of TME-mediated immunosuppression has the potential to enhance vaccine immunogenicity. To this end, using an immunocompetent syngeneic AML murine model, we have shown that hypomethylating agents (HMAs) reverse critical aspects of the immunosuppressive TME, and that HMA + fusion vaccination enhances AML-specific immune responses and survival. The TIGIT-CD155 inhibitory checkpoint pathway is a novel pathway fostering tolerance in the innate and adaptive immune arms. Blockade of this pathway reverses tumor-mediated T cell quiescence and promotes DC and NK cell immune surveillance. We aimed to examine if TIGIT-CD155 pathway inhibition +/- HMA enhances vaccine potency in a murine model. Methods/Results: Using a syngeneic immunocompetent murine AML model, we first investigated the impact of functional TIGIT monoclonal (mAb) blockade +/- decitabine (DAC) +/- vaccine on immune modulation and murine survival. C57BL/6J mice were retro-orbitally inoculated with 5x104 TIB-49 murine AML cells. Animals treated with TIGIT mAb monotherapy had inferior survival as compared to those treated with DAC or DC/AML vaccine monotherapies. Mice treated with vaccine alone, vaccine + TIGIT mAb, and vaccine + DAC + TIGIT mAb had similar survival but each cohort had improved survival compared to untreated animals, suggesting a vaccine-mediated effect not further enhanced by TIGIT mAb. To this end, we sought to investigate if deleting CD155, the native receptor to TIGIT, would impact AML immunogenicity and murine survival. We determined that baseline expression of CD155 in the murine AML cell line, TIB-49, is 72% by Ab staining and flow cytometric analysis. Using CRISPR/cas9 technology, we generated a CD155 knockout TIB-49 cell line. Black mice were retro-orbitally inoculated with 5x104 CD155-deleted or control TIB-49 AML cells. Animals were treated with vaccine, DAC, or both therapies. BLI imaging was performed 1-2/week. Animals inoculated with CD155-deleted AML cells that were treated with both DAC and vaccine show no signs of disease and remain alive 80 days following inoculation as compared to mice treated with vaccine or DAC alone (Fig 1,2). Conclusions: We demonstrate that CD155-specific deletion from a murine AML cell line confers a survival advantage when mice are exposed to HMA + vaccine as compared to either agent alone. Studies including TCR repertoire analyses are underway to better understand the immunologic underpinnings of this findings as targeting this pathway has promising translational potential. Disclosures Rosenblatt: Parexel: Consultancy; Imaging Endpoint: Consultancy; Celgene: Research Funding; BMS: Research Funding; Amgen: Other: Advisory Board; Merck: Other: Advisory Board; BMS: Other: Advisory Board ; Dava Oncology: Other: Education; Partner Tx: Other: Advisory Board. Kufe:Genus Oncology: Equity Ownership; Nanogen Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Canbas: Consultancy, Honoraria; Hillstream BioPharma: Equity Ownership; Victa BioTherapeutics: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Consultancy, Equity Ownership, Honoraria. Avigan:Takeda: Consultancy; Parexel: Consultancy; Janssen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partners Tx: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.
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张, 雨生. "The Expression of CD155 on Renal Cell Carcinoma Cells." Advances in Clinical Medicine 09, no. 03 (2019): 373–81. http://dx.doi.org/10.12677/acm.2019.93057.
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Arruga, Francesca, Andrea Iannello, Nikolaos Ioannou, Alberto Maria Todesco, Marta Coscia, Riccardo Moia, Gianluca Gaidano, et al. "The Tigit/CD226/CD155 Immunomodulatory Axis Is Deregulated in CLL and Contributes to B-Cell Anergy." Blood 138, Supplement 1 (November 5, 2021): 3718. http://dx.doi.org/10.1182/blood-2021-150183.
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Abstract BACKGROUND. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on T, NK and NKT cells, sharing structural and mechanistic similarities with PD-1 and CTLA-4. TIGIT competes with CD226, its partner receptor, for the binding to CD155 ligand: signaling triggered upon CD155 binding to CD226 potentiates T cell receptor (TCR) signaling and CD8 + T cell cytotoxicity against tumor cells (positive signaling). On the contrary, concomitant TIGIT expression on the cell surface prevents CD226 activation either by sequestering CD155 or by impeding CD226 homodimerization and phosphorylation (negative signaling). Recently, TIGIT was shown to be expressed on the surface of normal memory B cells, where it could directly act to suppress T cell responses. No data are available on TIGIT or CD226 expression by chronic lymphocytic leukemia (CLL) cells. AIM AND METHODS. Our aim was to investigate expression of the TIGIT and CD226 receptors and of the CD155 ligand in a cohort of clinically and molecularly annotated CLL patient samples. To this end, we designed a multiparametric panel of antibodies for flow cytometry and examined expression of the TIGIT/CD226/CD155 axis in peripheral blood mononuclear cells (PBMC) from our patient cohort. To investigate the impact of TIGIT/CD226 engagement on B cell responses, purified leukemic B cells were activated either through the B cell receptor (BCR) using an αIgM polyclonal antibody or with CpG oligonucleotide and interleukin 15 (IL-15) to induce proliferation. In selected experiments, we added recombinant human (Rh) TIGIT-Fc or CD155-Fc chimeras and αTIGIT or αCD226 blocking antibodies to interfere with this axis. RESULTS. Surface expression of TIGIT, CD226 and CD155 was evaluated in a cohort of 115 CLL samples and compared to age- and sex-matched healthy subjects. Both TIGIT and CD226 were upregulated on leukemic B cells compared to normal B lymphocytes, while CD155 was expressed at lower levels. A similar trend was observed on CD4 + and CD8 + T lymphocytes. High-risk CLLs (unmutated IgV genes, unfavorable cytogenetics and advanced stage) were predominantly TIGIT low and CD226 high, indicating an unbalance towards "positive signaling". Results were confirmed by confocal microscopy analyses on lymph node (LN) biopsies, which showed i) an overall higher TIGIT expression in CLL compared to reactive LNs and ii) among CLL LNs a stronger TIGIT positivity in mutated vs unmutated cases, confirming flow cytometry data. In line with these findings, Richter's syndrome samples and patient-derived xenografts models showed the lowest TIGIT and the highest CD226 levels. We next examined TIGIT axis expression during the follow up of CLL cases who underwent treatment with BTK inhibitor (BTKi). While CD226 levels remained unmodified upon treatment, a sharp decrease in surface TIGIT was detected soon after BTKi initiation. Since TIGIT acts by decreasing TCR signaling to shut down T cell responses, we hypothesized similar functions in B cells. By crosslinking the BCR with an αIgM antibody in a selected cohort of IGHV UM CLL cells, we found that BTK phosphorylation was induced to a lesser extent in TIGIT high compared to TIGIT low samples, suggesting that TIGIT is a marker of CLL cell anergy. Accordingly, interruption of receptors/ligand interactions with RhTIGIT-Fc chimera or with αTIGIT or αCD226 blocking antibodies, modulated BCR signaling capacity. Specifically, in TIGIT high samples, preventing receptor engagement by CD155 increased αIgM-induced BTK phosphorylation; in contrast, in TIGIT low samples, blocking CD155 interaction affected mostly CD226 signaling, thereby depotentiating BCR activation. Similar results were obtained when stimulating CLL cells with CpG/IL-15. Interestingly, we observed a significant upregulation of surface CD226 in CLL cells cultured for 6 days in the presence of CpG/IL-15. CONCLUSIONS. These results show for the first-time expression of TIGIT by CLL cells. Furthermore, they indicate that TIGIT is a marker of CLL cells anergy, whereas activated CLL cells express high levels of CD226. Inhibition of TIGIT binding to CD155 partially restores B cell signaling and activation. Future studies are needed to gain insights on the mechanisms behind its deregulation and to obtain a complete functional characterization of the axis. Disclosures Coscia: AbbVie: Honoraria, Other; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria; Gilead: Honoraria. Gaidano: Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Allan: Genentech: Consultancy, Research Funding; Epizyme: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Celegene: Research Funding; AstraZeneca Pharmaceuticals LP, Genentech, a member of the Roche Group, Janssen Biotech Inc, TG Therapeutics Inc.: Research Funding; AbbVie Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Janssen Biotech Inc, Pharmacyclics LLC: Consultancy; AbbVie Inc, Ascentage Pharma, Epizyme, Genentech, a member of the Roche Group, Janssen Biotech Inc, Pharmacyclics LLC: Other: Advisory Committee; TG Therapeutics: Research Funding. Furman: Oncotracker: Consultancy; Verastem: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; Sunesis: Consultancy; Incyte: Consultancy; Beigene: Consultancy; Acerta/AstraZeneca: Consultancy; Loxo Oncology: Consultancy; Genentech: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; TG Therapeutics: Consultancy; X4 Pharmaceuticals: Consultancy; Janssen: Consultancy, Honoraria; AstraZeneca: Honoraria. Deaglio: Heidelberg Pharma: Research Funding; Astra Zeneca: Research Funding.
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Ducoin, Kathleen, Linda Bilonda-Mutala, Cécile Deleine, Romain Oger, Emilie Duchalais, Nicolas Jouand, Céline Bossard, Anne Jarry, and Nadine Gervois-Segain. "Defining the Immune Checkpoint Landscape in Human Colorectal Cancer Highlights the Relevance of the TIGIT/CD155 Axis for Optimizing Immunotherapy." Cancers 14, no. 17 (August 31, 2022): 4261. http://dx.doi.org/10.3390/cancers14174261.
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While immune checkpoint (IC) therapies, particularly those targeting the PD-1/PD-L1 axis, have revolutionized the treatment of melanoma and several other cancers, their effect remains very limited in colorectal cancer (CRC). To define a comprehensive landscape of ICs in the human CRC tumor microenvironment (TME), we evaluated, using multiparametric flow cytometry, their ex vivo expression via tumor-infiltrating lymphocytes (TILs) (n = 40 CRCs) as well as that of their respective ligands on tumor and myeloid cells (n = 29). Supervised flow cytometry analyses showed that (i) most CD3+ TILs expressed PD-1 and TIGIT and, to a lesser extent, Tim-3, Lag3 and NKG2A, and (ii) EpCAM+ tumor cells and CD11b+ myeloid cells differed in their IC ligand expression profile, with a strikingly high expression of CD155 by tumor cells. An in situ analysis of IC and their ligands using immunohistochemistry on paraffin sections of CRC confirmed the overexpression of TIGIT and its ligand, CD155, in the TME. Most interestingly, an unsupervised clustering analysis of IC co-expression on CD4+ and CD8+ TILs identified two tumor subgroups, named IChigh and IClow. Altogether, our findings highlight the TIGIT/CD155 axis as a potential target that could be used in combination IC therapy in CRC.
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Mori, Kohei, Kazumasa Matsumoto, Noriyuki Amano, Dai Koguchi, Soichiro Shimura, Masahiro Hagiwara, Yuriko Shimizu, Masaomi Ikeda, Yuichi Sato, and Masatsugu Iwamura. "Expression of Membranous CD155 Is Associated with Aggressive Phenotypes and a Poor Prognosis in Patients with Bladder Cancer." Cancers 14, no. 6 (March 19, 2022): 1576. http://dx.doi.org/10.3390/cancers14061576.
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Objective: To investigate the relationship between clinicopathological findings and membranous CD155 (mCD155) or cytoplasmic CD155 (cCD155) expression in bladder cancer (BC). Methods: We retrospectively analyzed 103 patients with BC who underwent radical cystectomy between 1990 to 2015 at Kitasato University Hospital. Immunohistochemical staining was performed to evaluate CD155 expression in tumor cells. Cases with > 10% expression on the membrane or cytoplasm of tumor cells were positive. The Fisher′s exact test was used for categorical variables and the Kaplan–Meier method was used for survival outcomes. Univariate and multivariate Cox regression hazard models were used to evaluate the survival risk factors. Results: Cases that were mCD155-positive were associated with high-grade tumors (p = 0.02), nodal status (p < 0.01), and pT stage (p = 0.04). No association with any clinicopathological factor was observed in the cCD155 cases. Kaplan–Meier analysis showed that mCD155-positive cases had shorter periods of recurrence-free survival (p = 0.015) and cancer-specific survival (p = 0.005). Only nodal status was an independent predictor for both cancer-specific survival and recurrence-free survival in multivariate analysis (p = 0.02 and p < 0.01, respectively). Conclusion: mCD155 expression may be a marker of an aggressive phenotype and a poor prognosis in patients with BC.
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Mansorunov, Danzan, Natalya Apanovich, Pavel Apanovich, Fatimat Kipkeeva, Tatyana Muzaffarova, Anna Kuzevanova, Maxim Nikulin, Olga Malikhova, and Alexander Karpukhin. "Expression of Immune Checkpoints in Malignant Tumors: Therapy Targets and Biomarkers for the Gastric Cancer Prognosis." Diagnostics 11, no. 12 (December 16, 2021): 2370. http://dx.doi.org/10.3390/diagnostics11122370.
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To increase the effectiveness of anticancer therapy based on immune checkpoint (IC) inhibition, some ICs are being investigated in addition to those used in clinic. We reviewed data on the relationship between PD-L1, B7-H3, B7-H4, IDO1, Galectin-3 and -9, CEACAM1, CD155, Siglec-15 and ADAM17 expression with cancer development in complex with the results of clinical trials on their inhibition. Increased expression of the most studied ICs—PD-L1, B7-H3, and B7-H4—is associated with poor survival; their inhibition is clinically significant. Expression of IDO1, CD155, and ADAM17 is also associated with poor survival, including gastric cancer (GC). The available data indicate that CD155 and ADAM17 are promising targets for immune therapy. However, the clinical trials of anti-IDO1 antibodies have been unsatisfactory. Expression of Galectin-3 and -9, CEACAM1 and Siglec-15 demonstrates a contradictory relationship with patient survival. The lack of satisfactory results of these IC inhibitor clinical trials additionally indicates the complex nature of their functioning. In conclusion, in many cases it is important to analyze the expression of other participants of the immune response besides target IC. The PD-L1, B7-H3, B7-H4, IDO1 and ADAM17 may be considered as candidates for prognosis markers for GC patient survival.
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Zhong, Tingting, Xinghua Pang, Zhaoliang Huang, Na Chen, Xiaoping Jin, Yu Xia, Maxwell Zhongmin Wang, and Baiyong Li. "184 Two types of anti-TIGIT antibodies with distinct binding epitope and functional activities." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A198. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0184.
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BackgroundTIGIT is an inhibitory receptor mainly expressed on natural killer (NK) cells, CD8+ T cells, CD4+ T cells and Treg cells. TIGIT competes with CD226 for binding with CD155. In cancers, CD155 has been reported to up-regulate on tumor cells, and TIGIT was found to increase on TILs.1 Activation of TIGIT/CD155 pathway would mediate immunosuppression in tumor; while blockade of TIGIT promotes anti-tumor immune response.MethodsAK126 and AK113 are two humanized anti-human TIGIT monoclonal antibodies developed by Akesobio. Binding activity of AK126 and AK113 to human TIGIT, and competitive binding activity with CD155 and CD112, were performed by using ELISA, Fortebio, and FACS assays. Cross-reactivity with cynomolgus monkey TIGIT and epitope binning were also tested by ELISA assay. In-vitro assay to investigate the activity to promote IL-2 secretion was performed in mixed-culture of Jurkat-TIGIT cells and THP-1 cells.ResultsAK126 and AK113 could specifically bind to human TIGIT with comparative affinity and effectively blocked the binding of human CD155 and CD112 to human TIGIT. X-ray crystal structure of TIGIT and PVR revealed the C’-C’’ loop and FG loop regions of TIGIT are the main PVR interaction regions.2 The only amino acid residue differences in these regions between human and monkey TIGIT are 70C and 73D. AK126 binds to both human and monkey TIGIT, AK113 binds only to monkey TIGIT. This suggests that these residues are required for AK113 binding to human TIGIT, but not required for AK126. Interestingly, results from cell-based assays indicated that AK126 and AK113 showed significantly different activity to induce IL-2 secretion in mixed-culture of Jurkat-TIGIT cells and THP-1 cells (figure 1A and B), in which AK126 had a comparable capacity of activity to 22G2, a leading TIGIT mAb developed by another company, to induce IL-2 secretion, while, AK113 showed a significantly higher capacity than 22G2 and AK126.Abstract 184 Figure 1Anti-TIGIT Antibodies Rescues IL-2 Production in Vitro T-Cell Activity Assay in a dose dependent manner. Jurkat-TIGIT cells (Jurkat cells engineered to over-express human TIGIT) were co-cultured with THP-1 cells, and stimulated with plate-bound anti-CD3 mAb in the presence of TIGIT ligand CD155 (A) or CD112 (B) with anti-TIGIT antibodies. After incubated for 48h at 37° C and 5.0% CO2, IL-2 levels were assessed in culture supernatants by ELISA. Data shown as mean with SEM for n = 2.ConclusionsWe discovered two distinct types of TIGIT antibodies with differences in both epitope binding and functional activity. The mechanism of action and clinical significance of these antibodies require further investigation.ReferencesSolomon BL, Garrido-Laguna I. TIGIT: a novel immunotherapy target moving from bench to bedside. Cancer Immunol Immunother 2018;67:1659–1667.Stengel KF, Harden-Bowles K, Yu X, et al. Structure of TIGIT immunoreceptor bound to poliovirus receptor reveals a cell-cell adhesion and signaling mechanism that requires cis-trans receptor clustering. Proc Natl Acad Sci USA 2012;109:5399–5404.
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Vieira, Alexandre R., Ariadne Letra, Renato M. Silva, Jose M. Granjeiro, Takehiko Shimizu, Fernando A. Poletta, Juan C. Mereb, Eduardo E. Castilla, and Iêda M. Orioli. "PVR/CD155 Ala67Thr Mutation and Cleft Lip/Palate." Journal of Craniofacial Surgery 29, no. 2 (March 2018): 347–52. http://dx.doi.org/10.1097/scs.0000000000004159.
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O’Donnell, Jake S., Jason Madore, Xian-Yang Li, and Mark J. Smyth. "Tumor intrinsic and extrinsic immune functions of CD155." Seminars in Cancer Biology 65 (October 2020): 189–96. http://dx.doi.org/10.1016/j.semcancer.2019.11.013.
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Tao, Liang, Chaojun Song, Chenyang Huo, Yuanjie Sun, Chunmei Zhang, Xiaohua Li, Shaojuan Yu, et al. "Anti-CD155 and anti-CD112 monoclonal antibodies conjugated to a fluorescent mesoporous silica nanosensor encapsulating rhodamine 6G and fluorescein for sensitive detection of liver cancer cells." Analyst 141, no. 16 (2016): 4933–40. http://dx.doi.org/10.1039/c5an01908g.
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Sensitive detection of liver cancer cells using anti-CD155 and anti-CD112 monoclonal antibodies conjugated to ultrabright fluorescent mesoporous silica nanoparticles (FMSNs) encapsulating Rhodamine 6G and fluorescein was developed.
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Weiss, T., H. Meister, M. Weller, C. Sentman, and P. Roth. "PL2.1 Exploiting the DNAM-1 system for chimeric antigen receptor (CAR) T cell therapy of glioblastoma." Neuro-Oncology 21, Supplement_3 (August 2019): iii2. http://dx.doi.org/10.1093/neuonc/noz126.002.
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Abstract BACKGROUND Cancer immunotherapy with genetically engineered T cells that express a chimeric antigen receptor (CAR) has led to impressive responses in extracranial malignancies and is also explored against glioblastoma. However, CAR T cell strategies that are currently being explored against glioblastoma target single tumor antigens, which are non-homogeneously expressed and are prone to antigen escape. Furthermore, the immunosuppressive brain tumor microenvironment hampers anti-tumor efficacy. METHODS By immunohistochemistry and flow cytometry, we investigated the expression of CD155 and CD112, which are ligands to the activating immune cell receptor DNAX accessory molecule-1 (DNAM-1), in human and mouse glioma cell lines as well as in human glioblastoma samples. To understand their functional role, we generated CD155 or CD112 knock-out glioma cell lines using CRISPR/Cas9 and studied proliferation, sensitivity to irradiation or temozolomide as well as migration. To exploit the promiscuous binding features of DNAM-1, we generated different first or second-generation CAR T cells that use DNAM-1 as a tumor-binding domain. Subsequently, we investigated their anti-tumor activity in vitro in co-culture assays and in vivo in syngeneic orthotopic murine glioma models. RESULTS CD155 and CD112 are homogenously expressed in human and mouse glioma cell lines and human glioblastoma tissues. Knock-out of these ligands affected the migration of tumor cells, but did not affect proliferation or sensitivity to irradition or temozolomide. DNAM-1-based CAR T cells demonstrated high cytolytic activity and effector cytokine secretion in vitro. In vivo, DNAM-1 based CAR T cells reached to the tumor site in the brain upon intravenous administration, prolonged survival of orthotopic glioma-bearing mice and led to a durable anti-tumor response in a fraction of mice. The treatment was tolerated without toxicities. CONCLUSION We elucidated the tumor-intrinisic role of CD155 and CD112 and provide the first systematical preclincal assessment of DNAM-1 CAR T cells against glioma. These findings provide a rationale to test this immunotherapeutic strategy also in human glioma patients.
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Piovesan, Dana, Alejandra Lopez, Patrick Schweickert, Ferdie Soriano, Soonweng Cho, Ada Chen, Hema Singh, et al. "258 AB308 is an anti-TIGIT antibody that enhances immune activation and anti-tumor immunity alone and in combination with other I-O therapeutic agents." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A280. http://dx.doi.org/10.1136/jitc-2021-sitc2021.258.
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BackgroundTIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an inhibitory receptor expressed on natural killer (NK) cells, CD8< sup >+</sup > T cells, CD4< sup >+</sup > T cells and regulatory T cells (T < sub >regs</sub >). On the surface of these cells, TIGIT competes with another receptor, CD226, for shared receptor ligands (mainly CD155) that are expressed by cancer and antigen-presenting cells. Binding of CD155 to TIGIT results in immune suppression through multiple mechanisms. When TIGIT is blocked, binding of CD155 to CD226 promotes immune activation and anti-tumor immunity. We describe the preclinical characterization of AB308, a humanized wild-type IgG1 anti-TIGIT antibody that is currently undergoing clinical evaluation.MethodsBinding of AB308 to TIGIT and inhibition of the TIGIT/CD155 interaction were evaluated < i >in vitro</i >. Functional assays were used to evaluate the immunomodulatory activity of AB308 alone or in combination with zimberelimab (anti-PD-1) or etrumadenant (a small molecule A< sub >2a</sub >A< sub >2b</sub > adenosine receptor antagonist). Surrogate Fc-silent and Fc-enabled antibodies that recognize mouse TIGIT or PD-1 were leveraged to interrogate TIGIT biology in syngeneic mouse tumor models.ResultsHuman tumor-infiltrating lymphocytes from a variety of cancer types expressed appreciable levels of TIGIT on relevant immune populations, including tumor reactive CD39< sup >+</sup >CD103< sup >+</sup > CD8< sup >+</sup > T cells and T< sub >regs</sub >. AB308 has a high binding affinity for human TIGIT, potently blocks the TIGIT-CD155 interaction, and induces Fcγ receptor (FcγR)-mediated signaling. In line with FcγRIII binding, AB308 also demonstrated the ability to induce NK cell-driven antibody-dependent cell-mediated cytotoxicity against TIGIT-expressing target cells. AB308 significantly increased IL-2 secretion by peripheral blood mononuclear cells activated with superantigen A, an activity that was further enhanced with zimberelimab. Blocking TIGIT with AB308 potently activated CD226 signaling in Jurkat T cells co-cultured with CD155-expressing cells, and combination of AB308 with etrumadenant in this system abrogated adenosine-mediated T cell suppression that occurred even in the presence of checkpoint inhibition. In mice, while combining Fc-silent or Fc-enabled anti-mouse TIGIT antibody with anti-PD-1 resulted in greater tumor growth inhibition than with anti-PD-1 alone, the activity of Fc-enabled anti-TIGIT was associated with intratumoral T< sub >regs</sub >depletion.ConclusionsAB308 is a potent and highly effective anti-TIGIT antibody. Concurrent blockade of multiple immune checkpoints has the potential to confer effective and durable responses in the treatment of cancer. The data presented here support the clinical use of AB308 and provides a rationale for combination with zimberelimab and adenosine pathway blocking agents such as etrumadenant and CD73 small molecule inhibitor, AB680.Ethics ApprovalAnimal experiments were performed at Arcus Biosciences, Inc. in accordance with federal, state and Institutional guidelines and were approved by Arcus’ Institutional Animal Care and Use Committee.
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Frazier, Victoria N., Eda Holl, Michael Brown, David Boczkowski, Karenia Landa, Shelley Hwang, Matthias Gromeier, and Smita K. Nair. "Oncolytic poliovirus immunotherapy for breast cancer." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 249.25. http://dx.doi.org/10.4049/jimmunol.204.supp.249.25.
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Abstract Oncolytic poliovirus PVSRIPO is a recombinant, non-pathogenic polio:rhinovirus chimera that enters cells via the poliovirus receptor CD155. CD155 expression is virtually universal in solid cancers, including breast cancer. CD155 is also expressed on myeloid cells. PVSRIPO infection of antigen-presenting cells (APC), including dendritic cells (DC) and macrophages, induces type I interferon and APC activation. Intratumor injection of PVSRIPO results in robust T cell infiltration and generates an immune-engaged tumor microenvironment. PVSRIPO is therefore an ideal therapeutic complement to immune checkpoint inhibitors, such as anti-PD1/PDL1. We tested the hypothesis that blocking PD1/PDL1 in conjunction with PVSRIPO will potentiate durable antitumor immunity in the murine E0771 orthotopic breast cancer immunotherapy model. Intratumor injection of PVSRIPO in 5–7 mm orthotopic tumors induces rapid recruitment of neutrophils followed by infiltration of DC, T cells and B cells. Next, we investigated PVSRIPO with PD1/PDL1 blockade. All treatment groups significantly inhibited tumor growth compared to PBS. There were no significant differences in tumor growth inhibition between PVSRIPO and anti-PD1/PDL1 monotherapies. Combination PVSRIPO+PD1/PDL1 blockade was significantly more effective than the monotherapies at controlling tumor growth. We also tested neoadjuvant PVSRIPO in E0771-tumor bearing mice. We observed that intratumor PVSRIPO followed by surgery effectively controls tumor growth and prevents tumor regrowth following tumor rechallenge, suggesting induction of a systemic immune response. We are now testing neoadjuvant PVSRIPO with anti-PD1/PDL1 in murine models of cancer.
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Fu, Rong, Ling Deng, Zhaoyun Liu, Hui Liu, and Zonghong Shao. "Study of Bone Marrow Mesenchymal Stem Cells Regulating NK Cells Function through Tigit/ CD226 in Patients with Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 2685. http://dx.doi.org/10.1182/blood-2021-152389.
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Abstract Introduction：Bone marrow microenvironment plays a significant supporting role in the proliferation, differentiation, migration, survival and drug resistance of myeloma cells. To detect the expression of the co-inhibitory receptor TIGIT and the co-stimulatory receptor CD226 on the surface of natural killer cells (NK cells) in multiple myeloma (MM) patients, and changes in the immune phenotypes and killing function of NK cells. Furthermore, to explore the underlying mechanism of bone marrow mesenchymal stem cells (BMSCs) regulating NK cells function through TIGIT/CD226 in patients with MM. The expressions of TIGIT, CD226, activated molecules NKG2D and CD107a and functional molecules IFN-γ and Perforin on the NK cells in bone marrow or peripheral blood were detedted by FCM. BMSCs and NK cells were co-cultured at a ratio of 1:4 in vitro, which was grouped according to different monoclonal antibodies (mAbs) added. After co-cultured, the changes in the expression of NKG2D, NKp30, NKp44 and CD69 of NK cells and IFN-γ concentration were examined by FCM. NK cells and U266 were co-cultured with different E:T ratio and the apoptosis of U266 was detected to evaluate the killing function of NK cells by FCM. The expressions of CD155 on BMSCs in the bone marrow were detected by FCM. The correlations between CD155 expression on BMSCs and the production of IFN-γ and Perforin in bone marrow NK cells, as well as clinical characteristics were analyzed. Results: 1. In bone marrow, expression of TIGIT was significantly higher in patients with NDMM than those in patients with CR and HC (both P values <0.01). CD226 was significantly lower in NDMM patients than those in patients with CR and HC (both P values <0.01). NK cell surface activated molecules NKG2D and CD107a, and functional molecules IFN-γ and Perforin were significantly decreased in NDMM (Fig. A). In peripheral blood, TIGIT, CD226 and above immune phenotype expression levels were basically consistent with the trend in bone marrow. 2. In co-culture experiments of BMSCs and NK cells, only added anti-TIGIT mAbs, compared to both added anti-TIGIT and CD226 mAbs, the immune phenotypes of NK cells significantly increased (Fig. B). And the concentration of IFN-γ in the co-culture supernatants also increased (Fig. C). 3. After co-cultured with BMSCs, NK cells were co-cultured again with U266 in vitro, the apoptosis level of U266 in TIGIT mAbs group increased than those in TIGIT+ CD226 mAbs group at different E: T ratio (Fig. D). 4. The expression of CD155, the ligand of TIGIT and CD226, increased notably on the surface of BMSCs in MM patients(P<0.01) (Fig. E). 5. The expression of CD155 on BMSCs was negatively correlated with the production of IFN-γ and perforin in bone marrow NK cells with NDMM patients. And it has correlation with clinical characteristics including β2-MG, LDH, ALB, Hb, ISS stage and R-ISS stage in patients with MM. Summary: BMSCs may regulate NK cells through TIGIT/CD226. High expression of TIGIT on NK cells may mediate the inhibitory effect of BMSCs in MM patients. Blocking TIGIT could restore NK cells activation and killing function. CD155, a common ligand of TIGIT and CD226, was overexpressed on BMSCs in NDMM patients, but was low expressed on bone marrow MM cells. And it has correlation with NK cells function and clinical characteristics, indicating that CD155 may be involved in the regulation of NK cells function by BMSCs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Seth, S., I. Ravens, C. W. Lee, S. Glage, A. Bleich, R. Forster, G. Bernhardt, and C. Koenecke. "Absence of CD155 aggravates acute graft-versus-host disease." Proceedings of the National Academy of Sciences 108, no. 10 (February 14, 2011): E32—E33. http://dx.doi.org/10.1073/pnas.1017969108.
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Iguchi-Manaka, Akiko, Genki Okumura, Hiroshi Kojima, Yukiko Cho, Rei Hirochika, Hiroko Bando, Toyomi Sato, et al. "Increased Soluble CD155 in the Serum of Cancer Patients." PLOS ONE 11, no. 4 (April 6, 2016): e0152982. http://dx.doi.org/10.1371/journal.pone.0152982.
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Masson, D. "Overexpression of the CD155 gene in human colorectal carcinoma." Gut 49, no. 2 (August 1, 2001): 236–40. http://dx.doi.org/10.1136/gut.49.2.236.
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Freistadt, M. S., and K. E. Eberle. "Physical association between CD155 and CD44 in human monocytes." Molecular Immunology 34, no. 18 (December 1997): 1247–57. http://dx.doi.org/10.1016/s0161-5890(98)00003-0.
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