Checkpoints and Immunomodulation最新文献

{"title":"Abstract A26: De novo epigenetic programming restrains PD-1 blockade-mediated T cell rejuvenation","authors":"Hazem E. Ghoneim, Yiping Fan, A. Moustaki, Hossam A. Abdelsamed, P. Dash, P. Dogra, R. Carter, Walid Awad, G. Neale, P. Thomas, Ben Youngblood","doi":"10.1158/2326-6074.TUMIMM17-A26","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A26","url":null,"abstract":"Immune checkpoint blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. Given that many of the impaired effector properties of terminally exhausted CD8 T cells appear to be heritably maintained even in the absence of antigen, we investigated the role of de novo DNA methylation programming as a cell-intrinsic mechanism for establishing the ICB-nonresponsive state of T-cell exhaustion. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells. Therapeutic approaches to reverse these programs can enhance ICB-mediated T cell rejuvenation and ultimately facilitate the control of chronic viral infections and tumor growth. These data establish de novo DNA methylation programming as a regulator of T cell exhaustion and barrier of ICB therapy. Citation Format: Hazem E. Ghoneim, Yiping Fan, Ardiana Moustaki, Hossam Abdelsamed, Pradyot Dash, Pranay Dogra, Robert Carter, Walid Awad, Geoff Neale, Paul G. Thomas, Ben Youngblood. De novo epigenetic programming restrains PD-1 blockade-mediated T cell rejuvenation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A26.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79981439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A39: Viral response markers in immune-competent solid tumors by immunohistochemistry","authors":"G. Hostetter, Liu Minmin, Marie Mustert, Bree D. Berghuis, L. Turner, Peter A. Jones, S. Baylin, S. Jewell, L. Sempere","doi":"10.1158/2326-6074.TUMIMM17-A39","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A39","url":null,"abstract":"Background: Immune checkpoint blockade remarkably provides durable clinical response in solid tumors and immunohistochemistry (IHC) measures are current companion diagnostics. Currently four (4) IHC companion diagnostics of Programed Death Ligand (PD-L1) are components of FDA approved clinical trials. The marked clinical responses seen in checkpoint inhibition outpace basic science advances. Our previous reports of interferon mediated viral response against dsRNA intermediates, namely in colon and bladder cancer, have examined the role of global demethylation (5-AZA) and combination therapies. Materials and Methods: Cell lines HCT116 (colon) and T24 (bladder) were treated with single and combination therapy o f 5-AZA and Vitamin C were formalin fixed and processed for IHC staining for Ki67, MHL1 and markers of viral response: dsRNA markers (K1, J2), interferon activation (RIG I, MDA5, IFIT1, IFI27, IRF7, IRF9, and pSTAT1. Immune related markers included CD4, CD8, CD68, CD163 and PD-L1 (clone SP263). TMA sections were stained by automated immunostainers to include a subset of patient-matched whole sections. IHC staining documented for protein abundance (intensity 0-3) and cellular localization (nuclear, cytoplasmic, membranous) Results: Colon cell line experiments confirmed viral response activation with correlative staining of dsRNA antibodies with viral response markers RIG1, MDA5, IFIT1, IFI27, IRF7 and pSTAT1 with robust staining in formalin fixed paraffin embedded (FFPE) tissues with the exception of IFI27 and RIG1. Immune and macrophage markers CD8, CD4, CD68, and CD163 showed variable correlation with viral response markers and PD-L1 staining heterogeneous and most prevalent in non-small cell lung cancer (34%). Of 3 MMR deficient colon cancers, 2 stained positive for PD-L1. MDA5 staining was present in tumor and stroma but stronger peri-tumoral suggesting relation to tumor infiltrating lymphocytes. TMA cores and corresponding whole sections with co-expressed PD-L1 and MDA5 showed marked diminished CD8 staining as verified by nuclear quantitative algorithm. Summary: Here we evaluate the viral response phenotype via global demethylation in solid tumors with emphasis on colon and bladder cancer. lung and breast cancer. IHC methods in cell lines and FFPE clinical tissues provide a robust strategy to link viral and immune response in clinical tissue samples and provides glimpses of viral and immune pathways that might better elucidate tumor biology and thereby predict tumor response to drug regimens that include checkpoint inhibitors. Citation Format: Galen Hostetter, Liu Minmin, Marie Mustert, Bree Berghuis, Lisa Turner, Peter Jones, Steve Baylin, Scott Jewell, Lorenzo Sempere. Viral response markers in immune-competent solid tumors by immunohistochemistry [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstrac","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80213393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A35: BRAF inhibition increases exosomal PD-L1 protein expression in melanoma","authors":"Gyulnara G. Kasumova, Alvin Shi, J. Cintolo-Gonzalez, I. Chein, Dennie T. Frederick, Roman Alpatov, W. Michaud, D. Plana, D. Panka, R. Corcoran, K. Flaherty, R. Sullivan, Manolis Kellis, G. Boland","doi":"10.1158/2326-6074.TUMIMM17-A35","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A35","url":null,"abstract":"Background: Modulation of the PD-1/PD-L1 axis in melanoma is of critical importance in both the setting of targeted therapy treatment, as well as in newer trials combining targeted therapy with checkpoint blocking antibodies. BRAF inhibition has been shown to increase PD-L1 expression in melanoma tumors. Exosomes are circulating microvesicles that contain a subtranscriptome and/or subproteome of their cell of origin, including tumor cells and immune cells. We evaluated melanoma exosomal PD-L1 protein expression and the effect of BRAF inhibitor (BRAFi) treatment on exosomal PD-L1 protein levels. Methods: Melanoma cell lines (BRAFi sensitive [A375] and resistant [RPMI7951; induced resistant A375]) and patient plasma were used for analysis. Exosomal vesicles were isolated using centrifugation. Functional proteomics by reverse phase protein array (RPPA) were performed in cell lines and exosomes. RPPA PD-L1 results were quantified in cells and exosomes treated with control (DMSO) and BRAFi (PLX-4720). Exosomal PD-L1 expression from serial patient plasma with metastatic melanoma were assessed using ELISA prior to and after initiation of anti-PD-1 therapy. Results: Functional proteomic analysis revealed PD-L1 expression on both BRAFi sensitive and resistant cell lines. Cell line derived exosomes demonstrated enrichment of PD-L1 expression compared to their cell of origin, with significantly higher levels of expression in resistant lines and upon treatment with BRAFi therapy. Exosomes derived from patients with melanoma also revealed pre-treatment and on-treatment PD-L1 expression. Furthermore, consistent with cell line data, in a representative patient treated with BRAFi therapy prior to anti-PD-1 therapy, exosomal PD-L1 protein expression increased dramatically upon treatment with BRAFi and preceded a complete response to anti-PD-1 therapy. All other patients were treated only with checkpoint blockade and the majority demonstrated correlation of PD-L1 protein expression with tumor burden. Conclusions: These results confirm that exosomes from cell lines and patient samples express PD-L1 that can be serially monitored, and that treatment with BRAF inhibition results in increased PD-L1 levels, which in vitro are persistently elevated in BRAFi resistant cells. We also noted that exosomal PD-L1 protein expression levels tend to correlate with tumor burden in patient samples. Measuring PD-L1 expression may serve as a potential biomarker of tumor burden and as an inducible response to BRAFi therapy that predicts synergism with checkpoint anti-PD-1 therapy. Citation Format: Gyulnara G. Kasumova, Alvin Shi, Jessica A. Cintolo-Gonzalez, Isabel Chein, Dennie T. Frederick, Roman Alpatov, William A. Michaud, Deborah Plana, David J. Panka, Ryan B. Corcoran, Keith T. Flaherty, Ryan J. Sullivan, Manolis Kellis, Genevieve M. Boland. BRAF inhibition increases exosomal PD-L1 protein expression in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumo","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89983904","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A37: Immuno-oncological efficacy of RXDX-106, a novel TAM (TYRO3, AXL, MER) family small-molecule kinase inhibitor","authors":"Y. Yokoyama, E. Lew, C. Walsh, Jack Y. Lee, Joanne Oh, E. Tindall, R. Nevarez, Amy Diliberto, Heather A. Ely, Ruth Seelige, A. Albert, J. Bui, Gary Li","doi":"10.1158/2326-6074.TUMIMM17-A37","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A37","url":null,"abstract":"Background: The TAM family of receptor tyrosine kinases (RTKs), TYRO3, AXL, and MER, have emerged as attractive targets for cancer therapy. In cancer cells, overexpression of TAM RTKs is associated with resistance and a mesenchymal phenotype. In immune cells, TAM RTKs play a key homeostatic role as negative regulators of immune responses, contributing to the evasion of cancer cells from immune surveillance. RXDX-106 is a potent and selective TAM family inhibitor in preclinical development. Previously, in several syngeneic tumor models, we have demonstrated that RXDX-106 alone inhibited tumor growth, whereas such benefit was reduced when the tumors grew in immunocompromised athymic nude mice. In addition, RXDX-106 induced favorable polarization of the tumor infiltrating immune cells towards an anti-cancer phenotype. Here we sought (1) to evaluate the efficacy of RXDX-106 as a single agent and in combination with immune checkpoint inhibitors; (2) to identify the immuno-modulatory mechanisms of action; (3) to explore the reciprocal regulation of TAM expression on cancer and immune cells in the tumor microenvironment; and (4) to decipher how pharmacological inhibition of TAM signaling pathways on both tumor and immune cells would be beneficial, given their complex regulation and intimate relationship in the tumor microenvironment. Methods and Results: In the present study, we demonstrated that tumor growth inhibition in an MC38 model was associated with a significant increase in tumor associated M1 macrophages, an increase in CD169hi antigen presenting macrophages, and upregulation of PD-L1. In addition, we observed a higher ratio of CD8+/CD4+ T cells and increased expression of CD69 and PD-1 on CD8+ T cells, all indicative of activation of cytotoxic T cells. Finally, we observed an increase in Granzyme B and IFNγ with a concomitant decrease in VEGF in tumor cell lysates, evidence supporting T cell activation and M1 polarization of macrophages. Furthermore, in a CT26 syngeneic model, we demonstrated that RXDX-106 inhibited tumor growth as a single agent, and the effect was further potentiated by combination therapy with immune checkpoint inhibitors, as evidenced by upregulation of anti-tumor gene expression patterns, upregulation of anti-tumor cytokines in the tumor cell lysates, and an increase in T cell function. Finally, in an AXL-driven tumor model, we demonstrated that AXL expressing tumors induced a pro-tumorigenic immune environment, and treatment with RXDX-106 resulted in complete tumor regression and re-polarization of macrophages towards an M1, anti-tumor phenotype. Conclusion: RXDX-106 has the potential to restore and enhance immune function in macrophages and T cells, resulting in repolarization of the immune response towards an anti-tumor microenvironment. The unique mechanism of activating both innate and adaptive immunity, plus regulating cross-talk between immune cells and tumor cells by RXDX-106 supports clinical development of RXDX-","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91388119","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A09: Impaired HLA Class I antigen processing and presentation as a mechanism of acquired Rrsistance to immune checkpoint inhibitors in lung cancer","authors":"K. Hastings, S. Gettinger, Choi Jungmin, A. Truini, I. Datar, R. Sowell, A. Wurtz, W. Dong, G. Cai, M. Melnick, J. Schlessinger, S. Goldberg, A. Chiang, I. Melero, J. Agorreta, L. Montuenga, R. Lifton, S. Ferrone, P. Kavathas, D. Rimm, S. Kaech, K. Schalper, R. Herbst, K. Politi","doi":"10.1158/2326-6074.TUMIMM17-A09","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A09","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) including programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) antagonist antibodies for lung tumors mark a new era of cancer therapeutics harnessing a patient’s immune system to induce durable antitumor responses. Despite their impressive activity in some patients, challenges remain as most tumors exhibit primary or acquired resistance (AR) to ICIs, and the biologic mechanisms for resistance are poorly understood. Using a collection of 14 ICI-resistant lung cancer samples, we investigated whether alterations in genes encoding components of the HLA Class I antigen processing and presentation machinery or interferon signaling pathways play a role in AR to PD-1 or PD-L1 antagonistic antibodies. Although we did not detect any recurrent mutations or copy number changes in our AR cohort, we noted one case of an acquired homozygous loss of B2M that resulted in lack of HLA class I expression on the cell surface in both the patient’s tumor sample and the corresponding patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. To test if B2m expression confers sensitivity to ICIs in vivo, we used a CRISPR-mediated approach to knockout B2m in an ICI-sensitive, murine lung cancer cell line and transplanted the cells into syngeneic, immunocompetent mice. We found that the B2m knockout tumors were resistant to ICI therapy in contrast to the wild type tumors. Furthermore, RNA-seq analysis of a subset of the samples in the acquired resistance to ICI cohort revealed an inflammatory tumor microenvironment with significant upregulation of the inhibitory receptors LAG-3 and PD-1 in tumor-infiltrating T cells at ICI resistance. Overall, these findings provide a novel system for the evaluation and screening of candidate genes for their ability to mediate AR to ICIs in vivo. Moreover, they also provide evidence for the disruption of HLA Class I antigen processing and presentation as a mechanism for escape from ICIs in lung cancer and provide information on the immune microenvironment in ICI-resistant tumors. Citation Format: Katherine Hastings, Scott Gettinger, Choi Jungmin, Anna Truini, Ila Datar, Ryan Sowell, Anna Wurtz, Weilai Dong, Guoping Cai, Mary Ann Melnick, Joseph Schlessinger, Sarah Goldberg, Anne Chiang, Ignacio Melero, Jackeline Agorreta, Luis Montuenga, Richard Lifton, Soldano Ferrone, Paula Kavathas, David Rimm, Susan Kaech, Kurt Schalper, Roy Herbst, Katerina Politi. Impaired HLA Class I antigen processing and presentation as a mechanism of acquired Rrsistance to immune checkpoint inhibitors in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A09.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82726835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A31: Reprogramming of tumor-associated macrophages by anti-Program Death Ligand 1 (PDL1)","authors":"Huizhong Xiong, M. Moskalenko, Ryan Rodriguez, S. Mittman, Michelle Yang, J. Kim, R. Barcelli","doi":"10.1158/2326-6074.TUMIMM17-A31","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A31","url":null,"abstract":"Tumor-associated macrophages play a vital role in shaping tumor environment and contribute to the cancer-immune set point. Immunotherapy such as aPD1/aPDL1 has demonstrated remarkable therapeutic efficacy on a variety of cancers through reinvigorating CD8+ T cells. However, its impact on macrophages largely remains unclear. Here by using mouse MC38 cancer model, we show that aPDL1 re-programs macrophages from M2-like to M1-like: it decreases Arginase-I (ARG1), an M2-like marker, and increases iNOS and MHCII, both M1-like markers, on macrophages. Next, we investigate the mechanism behind the reprogramming. We identify that IFNg from CD8+ T cells and NK cells is boosted by aPDL1 and is required for macrophage re-polarization. IFNg blockade abrogates this process. Finally, we examine additional cancer models and observe similar phenotypes in another aPDL1-responsive model, but not in a third, non-responsive model. We conclude that tumor associated macrophage is re-programmed from M2-like to M1-like following aPDL1 treatment, and that it is mediated by enhanced IFNg in the tumor environment. Our findings suggest macrophage reprogramming as a novel mechanism and an independent avenue to promote antitumor activity via modulation of the cancer-immune set point. Citation Format: Huizhong Xiong, Marina Moskalenko, Ryan Rodriguez, Stephanie Mittman, Michelle Yang, Jeong Kim, Rafael Cubas Barcelli. Reprogramming of tumor-associated macrophages by anti-Program Death Ligand 1 (PDL1) [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A31.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89505378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A40: Prevalence of TIGIT expression in normal tissues, inflammation, and cancer","authors":"A. Hinsch, M. Kluth, A. Lübke, A. Menz, T. Krech, S. Steurer, D. Höflmayer, G. Sauter, W. Wilczak, K. Fischer, R. Simon","doi":"10.1158/2326-6074.TUMIMM17-A40","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A40","url":null,"abstract":"Introduction: TIGIT (T-cell immunoreceptor with Ig and ITIM domains) is an immune checkpoint protein expressed on subsets of cytotoxic and regulatory T cells. TIGIT inhibiting drugs are currently being developed. The purpose of this study was to investigate the pattern of TIGIT expressing cells in normal tissues, inflammation and cancer. Methods: Monoclonal mouse antibodies were used for immunohistochemical TIGIT (Dianova, Hamburg, Germany) and PD1 (Abcam, Cambridge, UK, ab52587) analyses on formalin fixed paraffin embedded tissue sections from normal lymphatic tissues as well as selected inflammations and cancers. Results: In lymph nodes and tonsils, TIGIT positivity was seen in a large fraction of the germinal center T-cells. A high density of TIGIT positive T-cells also occurred in the marginal zone and in the interfollicular area. The analyses of selected inflammatory diseases revealed detectable TIGIT expression in a high proportion of T-lymphocytes in BCG induced cystitis and prostatitis, Hashimoto thyreoiditis, Lichen sclerosis of the penis, skin eczema, Crohn’s disease, and rheumatoid synovialitis. In all normal and inflammatory tissues, the pattern of TIGIT expression largely paralleled the pattern of PD1 expression. Three examples each of cancers types for which immune checkpoint inhibitors are already approved or extensively studied (melanoma, lung, kidney, bladder and colorectal cancer) were also analyzed. Here, the number of CD8 positive lymphocytes varied greatly between individual cases and the fraction of TIGIT and PD1 positive CD4 and CD8 positive lymphocytes varied considerably between cases. Conclusion: Expression of TIGIT is regularly seen in a large subset of T-cells and has a similar expression pattern as PD1. TIGIT’s frequent co-expression with PD1 in cytotoxic T-cells is consistent with TIGIT representing a clinically relevant druggable immune checkpoint regulator that potentially could be targeted in combination with PD1. Citation Format: Andrea Hinsch, Martina Kluth, Andreas M. Lubke, Anne Menz, Till Krech, Stefan Steurer, Doris Hoflmayer, Guido Sauter, Waldemar Wilczak, Kristine Fischer, Ronald Simon. Prevalence of TIGIT expression in normal tissues, inflammation, and cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A40.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76283173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA30: Immune checkpoint blockade in cancer therapy: New insights and opportunities, and prospects for cures","authors":"J. Allison","doi":"10.1158/2326-6074.tumimm17-ia30","DOIUrl":"https://doi.org/10.1158/2326-6074.tumimm17-ia30","url":null,"abstract":"","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85683595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A11: Ipilimumab protects T cells from the antiproliferative effects of dexamethasone","authors":"Amber J. Giles, Marsha-Kay N. D. Hutchinson, H. Sonnemann, Caitlin M. Reid, Jinkyu Jung, Wei Zhang, Hua Song, R. Bailey, Dionne L Davis, Deric M. Park, M. Roederer, M. Gilbert","doi":"10.1158/2326-6074.TUMIMM17-A11","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A11","url":null,"abstract":"Background: Checkpoint inhibitor blockade, designed to activate antitumor immune cells, is gaining enthusiasm as a potential treatment modality for patients with brain tumors. However, adjuvant therapies aimed at killing tumor (i.e., chemotherapy) or reducing tumor-related edema (i.e., corticosteroids) are often cytotoxic to lymphocytes. Yet, whether tumor-specific T cells are harmed during corticosteroid treatment is not known. Methods: The effects of dexamethasone on healthy donor T cells was tested in vitro for T cell proliferation, cell cycle analysis, glucose uptake, transcriptional changes, and protein expression. The effects of dexamethasone and CTLA-4 antibody blockade were tested in vivo using the GL261 murine glioblastoma model. Results: Here we show that dexamethasone blocks proliferation of naive human T cells but not memory T cells. We find that dexamethasone inhibits early stages of T cell proliferation by impairing CD28-mediated cell cycle entry. Dexamethasone induced a fourfold increase in surface CTLA-4 during T cell stimulation, and neutralizing CTLA-4 with ipilimumab overcame the dexamethasone-induced blockade of cell cycle entry in vitro. Further, CTLA-4 blockade in combination with dexamethasone provided a survival benefit in vivo to mice bearing orthotopic GL261 brain tumors. Intriguingly, early dexamethasone treatment afforded the greatest survival advantage Conclusions: These findings shed light on the T cell-specific effects of dexamethasone and suggest that antigen-experienced T cells are resistant to anti-proliferative effects of corticosteroids. These findings have important implications for patients receiving immune therapy who may benefit from the anti-inflammatory properties of dexamethasone. Citation Format: Amber J. Giles, Marsha-Kay N.M. Hutchinson, Heather Sonnemann, Caitlin M. Reid, Jinkyu Jung, Wei Zhang, Hua Song, Rolanda Bailey, Dionne Davis, Deric M. Park, Mario Roederer, Mark R. Gilbert. Ipilimumab protects T cells from the antiproliferative effects of dexamethasone [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A11.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74545739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A08: Combination with a novel STING agonist significantly improves efficacy of anti-PD1 therapy in mouse syngeneic tumor models","authors":"Samanthi A. Perera, E. KopinjaJohnny, Yanhong Ma, J. Laskey, K. Chakravarthy, L. Cui, Yiping Chen, J. Presland, Sharad K Sharma, Shuxia Zhao, J. Piesvaux, E. Minnihan, Heidi Ferguson, Hyun Woo, Ian Knemeyer, I. Kariv, A. Tse, S. Cemerski, J. Cumming, B. Trotter, B. Pan, G. Addona, B. Long","doi":"10.1158/2326-6074.TUMIMM17-A08","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A08","url":null,"abstract":"Activated STING (STimulator of INterferon Genes) bound to its natural ligand 2,3-cGAMP (cyclic guanosine-adenosine monophosphate), initiates type I interferon (IFN) and pro-inflammatory cytokine production. IFN upregulation is essential to promote antigen-specific CD8+ T-cell priming and leads to potent anti-tumor activity. To exploit this mechanism we synthesized a new STING agonist, MSA-1, that potently activates both mouse and human STING. Intratumoral (IT) administration of MSA-1 to MC38 syngeneic tumor-bearing mice increased tumor and plasma cytokine levels and was effective at driving complete responses (CRs) in 100% of the animals. Most surviving animals developed tumor-specific adaptive immune memory as demonstrated by robust protection against re-challenge with the same tumor type. Mechanistic studies in immune-deficient mice suggested that the initial antitumor activity is in part due to cytokine-driven cytotoxicity and/or other innate immune mechanisms, which may have contributed to some animals not developing an adaptive immune memory. Importantly, MSA-1 caused long-term tumor regressions or CRs in CT26 and B16-F10 tumor models, both of which are intrinsically resistant to single-agent therapy with a fully murinized anti-mouse PD-1 antibody (muDX400). The antitumor immune response in these models was further enhanced when treating the animals with MSA-1 in combination with muDX400. This combination restored T-cell responses in both blood and tumors of the treated mice and provided long-lived immunologic memory in a majority of the animals. Taken together, these data strongly support the development of STING agonists in combination with Keytruda (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single agent anti-PD-1 therapy. Citation Format: Samanthi A. Perera, Johnny E. Kopinja, Yanhong Ma, Jason Laskey, Kalyan Chakravarthy, Long Cui, Yiping Chen, Jeremy Presland, Sharad Sharma, Shuxia Zhao, Jennifer Piesvaux, Ellen C. Minnihan, Heidi Ferguson, Hyun Chong Woo, Ian Knemeyer, Ilona Kariv, Archie Tse, Saso Cemerski, Jared Cumming, B. Wesley Trotter, Bo-Sheng Pan, George H. Addona, Brian J. Long. Combination with a novel STING agonist significantly improves efficacy of anti-PD1 therapy in mouse syngeneic tumor models [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A08.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89167336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}