Checkpoints and Immunomodulation最新文献

{"title":"Abstract A21: Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway","authors":"A. Jaiswal, T. Bartkowiak, C. Ager, Renee L Chin, Chao-Hsien Chen, Pratha Budhani, Midan Ai, M. Reilley, Manu Sebastian, D. Hong, M. Curran","doi":"10.1158/2326-6074.TUMIMM17-A21","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A21","url":null,"abstract":"Purpose: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across multiple preclinical models of cancer. In the clinic, however, development of these agents has been stymied by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven anti-tumor immunity from hepatotoxicity. Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immune competent mice, with or without co-administration of checkpoint blockade, via measurement of serum transaminase levels, through imaging of liver immune infiltrates, and via qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines and chemokines. Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27, which is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage triggering transaminase elevation. FoxP3+ regulatory T cells limit liver damage and their removal dramatically exacerbates 4-1BB agonist hepatitis. Co-administration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation of myeloid cells to produce Interleukin-27. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis but yields equal or greater antitumor immunity. Citation Format: Ashvin R. Jaiswal, Todd Bartkowiak, Casey R. Ager, Renee Chin, Chao Hsien Chen, Pratha Budhani, Midan Ai, Matthew J. Reilley, Manu M. Sebastian, David Hong, Michael A. Curran. Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway [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 A21.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73902274","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 A29: Multimeric anti-human OX40 induces robust immune responses","authors":"Shravan Madireddi, Yanli Yang, Sherry H Yeh, Chen Gu, Patricia L. Sanchez, Randall J. Brezski, H. Chiu, H. Erickson, R. Cubas, G. Lazar, J. Kim","doi":"10.1158/2326-6074.TUMIMM17-A29","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A29","url":null,"abstract":"Agonistic antibodies to co-stimulatory members of the TNF Receptor Superfamily (TNFRSF) have demonstrated impressive antitumor immune responses in murine tumor models and are currently under investigation in the clinic. In order to induce efficient co-stimulatory signaling, the majority of TNFRSF members require supermolecular cluster formation on the immune cell surface. Recent studies have revealed that agonistic antibodies achieve this in part by Fcγ receptor (FcγR) mediated cross-linking, enabling antibodies to cluster the TNFRSF member expressed on the opposing immune cell. Agonistic antibodies to OX40 (CD134; TNFRSF4), which primarily target T cells are currently in clinical trials for cancer immunotherapy. However, as OX40 needs clustering for efficient signaling, these antibodies can only function in microenvironments where FcγR bearing cells are abundant. To overcome this limitation, we generated multimeric anti-human-OX40 antibodies, which cluster OX40 independent of FcγR mediated cross-linking. In vitro, we found that multimeric anti-OX40 induces robust signaling independent of FcγR. Compared to the bivalent antibodies, multimeric anti-OX40 generated superior immune responses in vaccination and tumor settings, in vivo. Together, multimeric antibody platforms have important implications for effective targeting of OX40 and possibly other TNFRSF members. Citation Format: Shravan Madireddi, Yanli Yang, Sherry Yeh, Chen Gu, Patricia L. Sanchez, Randall Brezski, Henry Chiu, Hans Erickson, Rafael A. Cubas, Gregory Lazar, Jeong Kim. Multimeric anti-human OX40 induces robust immune responses [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 A29.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75313068","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 A28: Tumor cell intrinsic BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands","authors":"Kimberly Mayes, Zeinab Elsayed, Aiman S Alhazmi, M. Waters, Suehyb G. Alkhatib, Mark Roberts, Carolyn Song, Kristen Peterson, Vivian Chan, Nikhil Ailaney, Pumoli Malapati, T. Blevins, Berislav Lisnić, C. Dumur, Joseph W. Landry","doi":"10.1158/2326-6074.TUMIMM17-A28","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A28","url":null,"abstract":"Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase (Hpse) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy. Citation Format: Kimberly Mayes, Zeinab Elsayed, Aiman Alhazmi, Michael Waters, Suehyb Alkhatib, Mark Roberts, Carolyn Song, Kristen Peterson, Vivian Chan, Nikhil Ailaney, Pumoli Malapati, Tana Blevins, Berislav Lisnic, Catherine Dumur, Joseph Landry. Tumor cell intrinsic BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands [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 A28.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"116 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77354976","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 IA32: Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination","authors":"J. Brody","doi":"10.1158/2326-6074.TUMIMM17-IA32","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-IA32","url":null,"abstract":"Checkpoint blockade therapy of cancer has had tremendous impact; still, only a subset of patients experience remissions. One hypothesis is that resistant tumors lack sufficient somatic mutational burden and thus, targetable tumor-associated antigens (TAA). To the contrary, we described that Hodgkin’s lymphoma, despite a high anti-PD1 response rate (~65-87%), has significantly fewer mutations (Reichel et al., Blood 2015) than highly mutated tumors, such as lung cancer (anti-PD1 response rate ~20%). Recent, seminal work confirms that the presence of dendritic cells (DC) capable of cross-presenting TAA correlates with tumor immunogenicity (Spranger et al., Proc Natl Acad Sci USA 2016). Our hypothesis is that checkpoint blockade is limited by the tolerogenic microenvironment, specifically, suboptimal cross-presentation of TAA by suitably activated dendritic cells (DC). If so, then checkpoint blockade will be potentiated by optimal recruitment, loading, and activation of cross-presenting DC at the tumor site. We and others have recently found that tumors—including lymphomas—evade immune clearance by active exclusion of DC. Despite progress in mechanistic understanding of this immune evasion, we still lack means to modulate the phenomenon and facilitate T-cell entry and destruction of tumors. We developed an early-phase trial (funded by Damon Runyon CRF) testing a unique, rationally designed in situ vaccine (ISV) comprising 1) Flt3L to recruit DC, 2) radiotherapy (XRT) to load Flt3L-mobilized DC with TAA, and 3) Toll-like receptor agonist (TLRa) to activate TAA-loaded DC for cross-presentation. Strikingly, we observed partial and complete systemic tumor regressions, including distant and untreated tumors, improving months after therapy, and even elimination of malignant B cells with sparing of healthy B cells, suggesting a systemic antitumor immune response. The trial is based on our preclinical dat,a which recapitulate the clinical findings and also show that the ISV cure rate (~40%) increases markedly by combination with PD1 blockade (80-90%). These data prompted a new trial combining ISV with PD1 blockade opening in 2018. Though PD1/PDL1 blockade is potentiated by in situ vaccination, it is possible that there may be other, even more effective checkpoints for combination. We have developed two separate, complementary screening approaches using a novel EGFP-specific, murine CD8 T cell to enrich or probe for novel tumor-expressed (“PD-L1-like”) checkpoint molecules and have identified candidates for validation. Ultimately, the screening can be performed in vivo in the context of various immunotherapies, including in situ vaccination, stem cell transplantation, or PD-1 blockade. Citation Format: Joshua D. Brody. Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80230240","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 A19: PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor","authors":"Kristen E. Pauken, Vikram R. Juneja, P. Sage, M. LaFleur, J. Kuchroo, A. Ringel, N. Ron-Harel, Seth Maleri, G. Freeman, Nicolas Chevrier, M. Haigis, A. Sharpe","doi":"10.1158/2326-6074.TUMIMM17-A19","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A19","url":null,"abstract":"Although PD-1 pathway inhibitors are revolutionizing cancer treatment, the mechanisms by which PD-1 regulates anti-tumor immunity are not fully understood. Following subcutaneous transplantation of MC38 adenocarcinoma tumor cells into mice, we show that complete loss of PD-1 selectively on CD8+ T cells improved metabolic activity and functions in the tumor microenvironment (TME). Since clinically PD-1 inhibitors likely act on T cells post-priming, we next deleted PD-1 after initial priming and restricted deletion to roughly 50% of cells. Loss of PD-1 led to T cell-intrinsic boosts in metabolism and CD8+ T cells that lost PD-1 after priming preferentially formed anti-tumor memory cells, suggesting PD-1 antagonizes memory formation. Unexpectedly, there was also a bystander effect that improved functions of PD-1 expressing CD8+ T cells in the TME. These data suggest that complete loss of PD-1 is not necessary for optimal tumor immunity, and that enhancing the functions of a subset of CD8+ T cells can promote an antitumor microenvironment and immunologic memory. Citation Format: Kristen E. Pauken, Vikram R. Juneja, Peter T. Sage, Martin W. LaFleur, Juhi R. Kuchroo, Alison Ringel, Noga Ron-Harel, Seth P. Maleri, Gordon J. Freeman, Nicolas Chevrier, Marcia C. Haigis, Arlene H. Sharpe. PD-1 modulation promotes antitumor immunity by improving metabolic fitness of both PD-1+ and PD-1- CD8+ T cells in the tumor [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 A19.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89185950","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 A17: Bromodomain and extraterminal proteins regulate PD-L1/PD-1 signaling in breast cancer.","authors":"G. Andrieu, G. Denis","doi":"10.1158/2326-6074.TUMIMM17-A17","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A17","url":null,"abstract":"Introduction: Breast tumors are massively infiltrated immune cells of both lymphoid and myeloid origin that exert an anti-tumor pressure to limit cancer progression. Tumor cells can escape immune clearance by expressing several molecules that constitute the immune checkpoints. Antibodies targeting the PD-L1/PD-1 pathway are being evaluated clinically for several cancers and show early success. However, the realization that not all patients respond well to immunotherapy suggests other modalities could be combined to improve efficacy. The bromodomain and extraterminal (BET) proteins BRD2, BRD3 and BRD4 are epigenetically acting co-regulators of transcription, and are critical for cancer proliferation and metastasis. Little is known about the molecular mechanisms that regulate PD-L1 and PD-1 expression. BRD4 is known to bind directly to the PD-L1 promoter; its targeting suppresses PD-L1 expression while increasing CD8+ T cell activity to limit progression in ovarian tumor models. Hypotheses: BET proteins regulate PD-L1 and PD-L2 expression in breast tumors and PD-1 in CD8+ T cells. BET proteins are effectors of proinflammatory cytokine signaling, regulating PD-L1/PD-1 signaling in the breast tumor microenvironment. Methods: We used different cellular models of breast cancer. We also collected human peripheral blood mononuclear cells matched with mammary adipose tissue from mammoplasty patients at Boston Medical Center to assess expression of immune checkpoint proteins in the breast microenvironment. Pan-BET protein inhibition was performed by JQ1 treatment. Alternatively, BET proteins were individually and specifically depleted by siRNA. PD-1 and PD-L1 expression were determined by qRT-PCR and flow cytometry. Cytokines and chemokines present in the blood or secreted by the mammary adipose tissue were profiled by multiplexed antibody capture assay. Results: BET proteins regulate PD-L1 expression by breast cancer cells. BRD2 and BRD4 expression correlate with PD-1 in activated circulating T cells and BET inhibition ablates activation-induced PD-1 expression. Co-culture of breast cancer cells with activated circulating T cells enhances expression of immune checkpoint proteins in both compartments. BET protein inhibition rescues these phenotypes. Conditioned media from mammary adipose tissue increase PD-1 in PBMCs. Peripheral and mammary adipose tissue inflammatory signatures associate with PD-1 expression in PBMCs, suggesting that local inflammation in the breast tumor microenvironment contributes to diminishing anti-tumor immune responses. Conclusion: BET proteins regulate the PD-L1/PD-1 pathway in breast cancer. Next-generation BET protein inhibitors may combine well with PD-1 or PD-L1-targeted immunotherapies in difficult-to-treat cancers. Personalized BET profiles could inform individual patient responses to BET proteins and immune checkpoint inhibitors. Therapeutic approaches that treat the microenvironment should be leveraged to maximize efficacy","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89422518","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 A30: Ron kinase inhibition to improve immunotherapy for breast cancer metastasis","authors":"Shuping Lai, Atakan Ekiz, A. Welm","doi":"10.1158/2326-6074.TUMIMM17-A30","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A30","url":null,"abstract":"Metastasis is the cause of death for nearly all types of cancer, including breast cancer. An exciting new area of research in metastatic breast cancer centers on immune therapy. Although new immune checkpoint blockade therapies have provided benefit for a fraction of patients tested so far, the majority of patients still do not respond to these drugs. A better understanding of how the immune system can be harnessed against metastatic breast cancer is required in order to improve patient outcomes in this area. We previously discovered that macrophage Ron receptor tyrosine kinase promotes breast cancer metastasis by inhibiting CD8+ cytotoxic T lymphocyte activity. We hypothesized that dual blockade of Ron activity and existing immune checkpoint molecules would unleash a more effective CD8+ T cell response to control or eliminate metastatic breast cancer. Our strategy would simultaneously disable tumor-mediated immune evasion mechanisms on both the innate and adaptive immune systems. To test the potential of combination therapy, the Ron inhibitor BMS-777607 and/or the immune checkpoint blocking agents anti-PD1 or anti-CTLA4, were administered in our mouse mammary tumor model to examine the effects on breast tumor progression. To examine Ron-specific effects of BMS-777607, we also examined the effect of genetic deletion of host Ron signaling activity in combination with immunotherapy. The anti-tumor immune response was comprehensively examined by multi-color flow cytometry and immunohistochemical staining for tumor-infiltrating lymphocytes (TILs). Our data suggest that the combination of Ron inhibition with immune checkpoint blockade may be an effective therapy in breast cancer. Citation Format: Shu Chin Alicia Lai, Atakan Ekiz, Alana Welm. Ron kinase inhibition to improve immunotherapy for breast cancer metastasis [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 A30.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90106856","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 A16: Epstein-Barr virus encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B cell lymphomas","authors":"Anastasiadou Eleni, Stroopinsky Dina, Stella Alimperti, Alan L Jiao, A. Pyzer, Claudia Cipitelli, M. Severa, Christopher S. Chen, S. Uccini, D. Avigan, A. Faggioni, P. Trivedi, F. Slack","doi":"10.1158/2326-6074.TUMIMM17-A16","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A16","url":null,"abstract":"Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Indeed, Epstein-Barr virus (EBV) positive Hodgkin’s lymphoma and gastric adenocarcinomas have higher Programmed Cell Death Ligand, PD-L1, expression. However, how EBV alters ICs in the context of its preferred host, the B lymphocyte and lymphomas, is unknown. Here, we used Burkitt lymphoma (BL), diffuse large B cell lymphomas (DLBCL) and their EBV infected or EBNA2 transfected derivatives to address this question. EBV latency III cells expressed high levels of PD-L1. In a DLBCL model, we found that EBNA2 but not LMP1 is sufficient to induce PD-L1. The upregulation of PD-L1 was confirmed in estrogen inducible EBNA2 carrying B lymphoma cells. Clinical samples from DLBCL patients showed that EBV infected, latency III cases expressed high levels of PD-L1. The PD-L1 targeting oncosuppressor miR-34a was downregulated in EBNA2 transfected cells. miR-34a reconstitution in EBNA2 expressing DLBCL reduced PD-L1 expression and increased their immunogenicity in 2D mixed lymphocyte reactions (MLR) and 3D microfluidic chip based MLRs. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for diagnosis and combinatorial immunotherapy approaches which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers. Citation Format: Anastasiadou Eleni, Stroopinsky Dina, Stella Alimperti, Alan Jiao, Athalia Pyzer, Claudia Cipitelli, Martina Severa, Christopher S. Chen, Stefania Uccini, David Avigan, Alberto Faggioni, Pankaj Trivedi, Frank J. Slack. Epstein-Barr virus encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B cell lymphomas [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 A16.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"100 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80334948","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 A12: Identification of resistance to immune checkpoint blockade","authors":"Shengqing Gu, Ziyi Li, Xia Bu, Xiaofang Xing, G. Freeman, Myles A. Brown, Xiaole Shirley Liu","doi":"10.1158/2326-6074.TUMIMM17-A12","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A12","url":null,"abstract":"Despite its enormous success in treating several types of cancer, including melanoma, lung cancer, renal cancer, bladder cancer, and Hodgkin’s lymphoma, immunotherapy still only induces responses in a subset of patients. Understanding the response and resistance mechanisms are still open questions. Based on the reported heterogeneous response to targeted therapies in multiple cell lines, we hypothesize that significant heterogeneity might also exist regarding the response to immune checkpoint blockade (ICB), which may manifest the mechanisms of response/resistance to ICB. To this end, we applied the ClonTracer barcoding system to assess the heterogeneity of response to anti-PD1 and anti-CTLA4 in CT26 colorectal cancer model. Surprisingly, whereas significant heterogeneity exists in the cell line’s ability to initiate cancer in vivo, ICB treatment did not lead to dramatic clonal enrichment compared to control treatment. Therefore, the tumor microenvironment and/or the epigenetic programs in cancer cells may dictate the response to ICB. Note: This abstract was not presented at the conference. Citation Format: Shengqing Stanley Gu Gu, Ziyi Li, Xia Bu, Xiaofang Xing, Gordon Freeman, Myles Brown, Xiaole Shirley Liu. Identification of resistance to immune checkpoint blockade [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 A12.","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87200160","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 A07: Changes in immune profiles of osteosarcoma dogs receiving a GD3-based vaccine concurrently with carboplatin chemotherapy and surgery","authors":"B. Sahay, S. Hutchison, Matt Cascio, A. Lejeune, C. Souza, A. Szivek, K. Shiomitsu, K. Harding, Stacey A Fox-Alvarez, Mia Livaccarri, L. Powers, R. Milner","doi":"10.1158/2326-6074.TUMIMM17-A07","DOIUrl":"https://doi.org/10.1158/2326-6074.TUMIMM17-A07","url":null,"abstract":"Introduction: The disialyl gangliosides GD2/GD3 have been implicated in the enhancement of malignancy in a number of human and animal cancers and as a tumor antigen target for immunotherapy. In a recent abstract presented at an AACR Conference we reported on the coexpression of GD2/GD3 in four canine osteosarcoma (OSA) cell lines (1). In a prospective IACUC approved clinical trial we vaccinated dogs with a GD3-based vaccine with naturally occurring OSA receiving surgery and carboplatin chemotherapy to investigate the expression profiles of immune modulating cells overtime. Methods: Dogs will be entered into the study only if they meet the following inclusion criteria: have a confirmed diagnosis of OSA and no other life-threatening diseases. The study will accrue 40 cases; 20 will receive the vaccine plus standard of care and 20 dogs will receive only the standard of care (amputation and intent to treat with 6 doses of carboplatin). On admission blood will be collected according to the protocol for monitoring of the immune response. The dogs will then be vaccinated according to a predetermined protocol during chemotherapy and staged. The immune response profile of the vaccine group will be compared to dogs receiving standard of care alone and normal dogs. Flow cytometric platforms were developed to monitor changes in immune cells (CD5, CD21, CD4, CD8, CD14, CD11b, MHCII, and Foxp3). In addition, IHC arrays and RNA Scope will be developed for checkpoints of immunity PD1, PDL-1 and expression of intratumoral immune cells. Results: Currently twenty dogs with osteosarcoma have enrolled into the study and have received standard of care and vaccination. Complete flow cytometric immune profiles are available for nine dogs with osteosarcoma. On admission, all dogs with OSA showed elevated cell counts of Treg (FoxP3+/CD4+) cells, Monocytic (m-) and Granulocytic (g-) myeloid derived suppressor cells (MDSCs) when compared to normal dogs (all dogs had normal CBCs). All m-MDCSs and g-MDSCs and Treg cells decreased significantly after the first dose of chemotherapy. Serial sampling over weeks showed sustained inhibition even after chemotherapy was completed (18 weeks). Two OSA cases which relapsed with metastasis to the lungs showed significant increases in Treg cells at the time of restaging. Complete necropsy post-therapy in three dogs showed changes in metastatic profiles; 2/3 showed no metastatic disease to the lungs, but metastases occurred to bone and kidneys. Discussion: MDSCs series of cells and Treg cells are increased in OSA compared to normal dogs and may be a factor in maintaining a welcoming tumor microenvironment and resistance to immunotherapy. MDSCs are reported to be elevated in other cancers, but not in naturally occurring OSA. Furthermore, canine OSA cell lines show increased expression of CCL2 and COX2 (data not shown). Recruitment of MDSCs to the cancer micro-tumor environment are thought to be mediated by the chemokine CCL2 and COX2. Abrog","PeriodicalId":9948,"journal":{"name":"Checkpoints and Immunomodulation","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87761328","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}