Regulating T-cells and Their Response to Cancer最新文献

{"title":"Abstract A168: Quiescent stem cells evade immune surveillance","authors":"Judith Agudo, M. Merad, Brian D. Brown","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A168","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A168","url":null,"abstract":"There is a long-standing interest in understanding the immunogenicity of adult stem cells due to their role in tissue homeostasis, regeneration and oncogenesis. Notably, their self-renewing capacity means they are long-lived, and can accumulate mutations over time, which would result in neoantigens. These neoantigens could make stem cells potential targets of T-cells. However, whether they are subject to immune surveillance is unknown. Here, we utilized a novel technology to study immune responses against virtually any cell type, along with specific stem cell mouse models, to interrogate the immunogenicity of adult stem cells in their niche in vivo. We found that immune privilege is not a general property of adult stem cells. Instead, our studies revealed that most epithelial stem cells, such as those in the gut and ovary, are subjected to immune clearance, but that highly quiescent stem cells escape immune detection. This is an intrinsic property of the resting stem cells resulting from downregulation of MHC class I and other key components of the antigen presentation machinery, which results in complete protection from immune attack. These studies established that quiescent tissue stem cells hide from immune surveillance and protect their integrity. This helps to understand why mutations in long-lived stem cells do not lead to immune clearance and suggests how cancer stem cells may evade immune surveillance. Citation Format: Judith Agudo, Miriam Merad, Brian D. Brown. Quiescent stem cells evade immune surveillance [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A168.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"41 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115347076","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 A209: Targeting immune cell-specific sphingosine-1-phosphate receptor 4 to restore antitumor immunity resulting in improved therapy response","authors":"Catherine Olesch, Evelyn Sirait-Fischer, B. Brüne, A. Weigert","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A209","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A209","url":null,"abstract":"The inflammatory tumor microenvironment is a critical element of tumor development and progression, as well as a parameter predicting the response to cancer treatment. An increased abundance of suppressive immune cells such as tumor-associated macrophages (TAMs) and regulatory T-cells (Tregs) appears thereby as a limiting factor for a successful treatment due to the inhibition of tumoricidal lymphocytes such as cytotoxic CD8+ T-cells. The bioactive lipid sphingosine-1-phosphate (S1P), which signals mainly through its five G-protein-coupled receptors (S1PR1-5), emerges as an important regulator of carcinogenesis that promotes tumor growth, angiogenesis and metastasis, among others, by affecting tumor immunity. We investigated S1PR4, which is exclusively expressed by immune cells, as a potential regulator of antitumor immunity. Using a transgenic mouse model of spontaneous invasive ductal mammary carcinoma (PyMT mice) and the AOM/DSS model of colitis-associated cancer, we show that S1PR4 deficiency (S1PR4-/-) leads to a significant decrease in lung metastasis and a delay of tumor growth in case of the PyMT breast cancer model and reduced colon tumor incidence and size in S1PR4-/- mice subjected to the AOM/DSS model. S1PR4-/- PyMT tumors contained macrophages with an altered activation profile, characterized by reduced IL-10, IL-1β and IL-6 production. Likely as a consequence, S1PR4-/- mice showed a less immunosuppressive lymphocyte infiltrate composed of reduced Tregs and Th17 cells, but increased cytotoxic CD8+ T-cell numbers. Interestingly, AOM/DSS-treated colons of S1PR4-/- mice also displayed a marked increase in CD8+ intestinal epithelial lymphocytes, underlining the negative impact of S1PR4 signaling on CD8+ T-cell abundance during tumor development. Next, we asked whether increased CD8+ T-cell numbers in S1PR4-/- tumors would increase the efficacy of chemotherapy or immunotherapy. Indeed, S1PR4-/- PyMT mice exhibited a significantly improved response to treatment with doxorubicin (DXR), characterized by the absence of relapse, whereas WT PyMT tumors relapsed after DXR treatment. This enhanced tumor control was strictly CD8+ T-cell dependent, as shown by experiments utilizing CD8 antibody depletion in combination with DXR treatment. Finally, using a MC38 colon adenocarcinoma model, where MC38 cells were engrafted into the flanks of WT and S1PR4-/- mice, we demonstrate a synergistic effect of S1PR4 depletion and anti-PD-1 immunotherapy reflected by reduced tumor growth and an increased survival rate of tumor-bearing S1PR4-/- compared to WT mice. A similar effect of additional tumor growth reduction by combinatorial anti-PD-1 treatment was seen in S1PR4-/- PyMT mice compared to their WT counterpart, although less pronounced compared to the MC38 allograft model. Taken together, our data indicate that S1PR4 depletion restores antitumor immunity by, among other mechanisms, increasing CD8+ T-cell abundance, translating into enhanced response to che","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"51 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"116559645","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 PR02: Neoadjuvant immunotherapy pre-cancer surgery relieves tumor-specific CD8+ T-cell dysfunction and restores memory differentiation potential","authors":"Jake S. O’Donnell, Jing Liu, Stacey Allen, S. Mueller, M. Smyth, M. Teng","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR02","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR02","url":null,"abstract":"Recent preclinical and clinical results indicate that neoadjuvant immunotherapy pre-surgery may be superior to surgery followed by adjuvant immunotherapy, however it is unclear why. Using preclinical mouse models of spontaneously metastatic cancer, we dissected the mechanisms underpinning the improved efficacy of neoadjuvant immunotherapy. Compared to adjuvant treatment, neoadjuvant treatment promoted the expansion, subsequent contraction, and memory differentiation of tumor-specific CD8+ T-cells. This process “resets” the antitumor immune response to one more reminiscent of that which occurs during an acute viral infection. These effects required the presence of the primary tumor followed by its timely resection but was independent of de novo priming of tumor-specific CD8+ T-cells. This understanding allowed us to identify an on-treatment biomarker within the blood that predicted long-term survival among neoadjuvant-treated mice. These findings may enable selective targeting of key pathways activated and further improvement of front-line cancer immunotherapies. Citation Format: Jake S. O9Donnell, Jing Liu, Stacey Allen, Scott Mueller, Mark J. Smyth, Michele W.L. Teng. Neoadjuvant immunotherapy pre-cancer surgery relieves tumor-specific CD8+ T-cell dysfunction and restores memory differentiation potential [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR02.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121971814","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 A219: Using poxvirus to improve immunotherapy for brain glioma","authors":"Bingtao Tang, Claire P. Schane, J. Shisler, E. Roy","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A219","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A219","url":null,"abstract":"Oncolytic viral immunotherapy is a novel approach to cancer treatment. Viruses can directly kill cancer cells, provide antigens to dendritic cells to stimulate a T-cell response, and make cancer cells express genes of immune-enhancing cytokines locally within the tumor microenvironment. We used two types of poxvirus, myxoma virus and vvDD vaccinia virus (double deletion of vaccinia growth factor and thymidine kinase), to deliver IL-15/IL-15Rα gene (a cytokine that boosts the immune system) into brain gliomas. We found that the numbers of NK cells and CD8+ T-cells in the tumor area greatly increased and viable cancer cells substantially decreased after the injection of vvDD-IL15/IL15Rα virus. Vaccination of GARC-1 (a neoantigen for mouse glioma) with CpG and Incomplete Freund’s Adjuvant twice before tumor implantation together with vvDD-IL15/IL15Rα virus, rapamycin and celecoxib treatment after tumor implantation eliminated the gliomas. In order to mimic the clinical situation of treatment beginning after establishment of the tumor, GARC-1 specific CD8+ T-cells were adoptively transferred into tumor-bearing mice; when combined with oncolytic poxvirus (either Myx-IL15/IL15Rα or vvDD-IL15/IL15Rα), rapamycin, and celecoxib, this treatment can also cure gliomas. We already confirmed that IL15/IL15Rα, adoptive transfer of GARC-1 specific T-cells and celecoxib are essential components in this combination treatment. Current studies are evaluating the mechanism and contributions of different components of the treatment. Citation Format: Bingtao Tang, Claire Schane, Joanna Shisler, Edward Roy. Using poxvirus to improve immunotherapy for brain glioma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A219.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"44 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"123785461","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 A170: Transient microbiota depletion enhances mucosal CD8 T-cell responses","authors":"Simone Becattini, A. Louie, I. Leiner, E. Pamer","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A170","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A170","url":null,"abstract":"CD8+ tissue resident memory T-cells (Trm) are poised for immediate reactivation in peripheral organs and have enhanced protective potential in comparison to circulating T-cells. Trm represent potential players in antitumor immunity that might be enhance the effectiveness of cancer vaccines. Vaccination strategies increasing accumulation of Trm cells in skin or in the genital tract augmented protection against tissue-specific pathogens in vivo. However, to date, no specific approach has been proposed to reinforce Trm in the intestinal mucosa. The microbiota shapes composition and functions of host immune populations, particularly in the intestinal tissue, where it determines the ratio between conventional and regulatory T-cells. This suggests that modulation of commensal communities might be exploited to augment numbers and function of gut-resident CD8 T-cells. Listeria monocytogenes attenuated strains are employed in clinical trials to promote immunity against tumor antigens and have been administered orally to healthy volunteers to promote mucosal immunity, proving safety of this approach. Developing more effective mucosal vaccination strategies based on oral administration of Listeria-based vectors, would have a great impact in the fight against tumors of the gastrointestinal tract, such as colorectal cancer, for which neoantigens are being discovered. Based on our recent observation that antibiotic treatment favors intestinal expansion of Listeria, we have devised an oral immunization strategy (TMDI, Transient Microbiota Depletion prior to Immunization) consisting of oral vaccination with an antigen-carrying Listeria strain following administration of a single dose of antibiotics. In mice, TMDI promoted expansion of engineered avirulent Listeria strains, resulting in striking expansion of the antigen-specific CD8+ Trm population (~20 fold), that additionally displayed potent effector functions. Mice immunized with this approach showed augmented protection upon rechallenge with high doses of pathogen.We found that increased accumulation of T-cells was dependent on both increased antigen load and stronger inflammatory stimuli; surprisingly, even when the vector was forcedly maintained at high levels in the intestinal lumen for several weeks, the elicited CD8+ Trm cells did not show any sign of exhaustion and retained the capacity to rapidly produce inflammatory cytokines upon antigen stimulation. In conclusion, we have identified a novel strategy to harness tissue resident CD8 T-cells against an epitope of choice by modulating microbiota density at the time of immunization, and set up a system to dissect the requirements for obtaining potent T-cell responses in the intestine. This tool can potentially be utilized to design improved vaccines against tumors of the intestinal tract. Citation Format: Simone Becattini, Alexander Louie, Ingrd M. Leiner, Eric Pamer. Transient microbiota depletion enhances mucosal CD8 T-cell responses [abstract]. In: Pr","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130181125","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 A220: Destabilizing domain technology facilitates exogenous regulation of IL15 and IL12 for adaptive T-cell therapy","authors":"K. Tran, Kutlu G. Elpek, T. Ezell, S. Heller, Mara C Inniss, A. Kulkarni, D. Li, Grace Y. Olinger, M. Ols, C. Reardon, Dexu Sun, Tariq Kassum, M. Briskin, C. Richardson, Vipin Suri, S. Shamah, M. Gilman","doi":"10.1158/2326-6074.cricimteatiaacr18-a220","DOIUrl":"https://doi.org/10.1158/2326-6074.cricimteatiaacr18-a220","url":null,"abstract":"Cytokines are messenger molecules that act as regulators of innate and adaptive immunity by propagating cell-cell immune signaling. Several cytokines have been approved for the treatment of metastatic renal cell cancer, advanced melanoma, and hairy cell leukemia (HCL) and can be particularly effective when combined with adoptive cell therapy. However, systemic delivery or constitutive expression of cytokines even at moderate levels can potentially lead to significant toxicity. These hurdles to enabling cytokine-enhanced adoptive cell therapy motivated us to implement destabilizing domain (DD) technology for regulating cytokines in chimeric antigen receptor (CAR) reprogrammed T-cells. The ability of CAR-T-cells to traffic to tumor sites enables localized co-delivery of cytokines for enhanced CAR-T-cell antitumor activity while improving safety. Obsidian Therapeutics’ DD technology enables titratable and reversible regulation of a protein of interest with FDA-approved small-molecule drugs in a time- and dose-dependent manner. Protein-fused DDs are misfolded in the absence of a stabilizing small-molecule ligand and are rapidly degraded by the proteasome. However, the addition of ligand restores the folding, stability, and function of the DD-protein fusion. We have generated IL-12 and membrane-bound IL15-IL15Ra (mbIL15) fused to DDs such as FK506 binding protein (FKBP), Escherichia coli dihydrofolate reductase (ecDHFR), as well as human protein substrates (huDDs) with clinically approved ligands. DD-IL12 and DD-mbIL15 fusions displayed ligand-dependent regulation of cytokine secretion or cell surface expression, respectively, in cell lines and primary human T-cells. We then tested DD regulation of IL12 or mbIL15 in vivo by injecting T-cells engineered with cytokine-fused DDs into NSG mice, followed by oral administration of vehicle or corresponding ligand. Vehicle-treated mice displayed low level expression of the respective cytokines, whereas ligand treatment robustly induced the expression of target cytokine within 4-6 hours after treatment. Cytokine expression returned to baseline levels 24 hours following ligand administration. These data demonstrate the feasibility of exogenous control over transgene-derived protein expression in primary human T-cells for the development of next-generation CAR-T-cell products with enhanced efficacy and more favorable safety profiles. Citation Format: Karen Tran, Kutlu Elpek, Tucker Ezell, Scott Heller, Mara Inniss, Abhishek Kulkarni, Dan Jun Li, Grace Olinger, Michelle Ols, Christopher Reardon, Dexue Sun, Tariq Kassum, Michael Briskin, Celeste Richardson, Vipin Suri, Steven Shamah, Michael Gilman. Destabilizing domain technology facilitates exogenous regulation of IL15 and IL12 for adaptive T-cell therapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer ","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130362834","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 A181: Origin of tumor-elicited cytotoxic innate-like T-cell responses","authors":"Chun Chou, Saïda Dadi, Briana G. Nixon, Ming Li","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A181","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A181","url":null,"abstract":"In most murine cancer models and human patients, cell-mediated cytotoxicity is critical for the destruction of tumor cells. Conventional CD8+ T-cells, which possess cytotoxic capacity, are thus the targets of most cancer immunotherapies. However, tumors that are poorly antigenic, immunosuppressive, or have low T-cell infiltration are often resistant to CD8+ T-cell-centric modalities. Thus, exploring the roles of other cytotoxic immune cell types will complement and synergistically enhance the potency of current treatments. Recently, our lab identified a population of tumor-infiltrating innate-like T-cells (ILTCs), which constitutively express high levels of cytotoxic molecules, are closely juxtaposed to tumor cells, and readily induce cytolysis of transformed target cells. Although armed with a polyclonal T-cell receptor (TCR) repertoire similar to conventional T-cells, ILTCs are phenotypically unconventional and innate-like by the concomitant expression of activating and inhibitory receptors typically found on natural killer (NK) cells but not on conventional T-cells. The specificity of ILTC TCR is unknown, and the extent to which TCR engagement maintains ILTCs and activates their effector functions in the context of tumor also remains ill-defined. While ILTCs and conventional T-cells share a thymic origin, genome-wide analyses revealed a distinct epigenetic landscape in ILTCs compared to conventional T-cells, suggesting that ILTCs constitute a disparate lineage and that alternative selection processes drive their fate choice during thymic development. Here, we showed that commitment to ILTC fate is instructed by distinct TCR specificity. Utilizing TCR retrogenic models and adoptive cell transfer approach, we identified the thymic and circulating ILTC-lineage-committed progenitor. These precursors are continuously generated by adult hematopoiesis and replenish the ILTC pool as the tumor develops. By acutely ablating TCRs, we demonstrated that tumor-resident ILTCs continuously require TCR for their maintenance. Together, our results delineate the ontogeny of ILTCs. Their unique TCR specificity, homing pattern, and innate-like features make ILTC a powerful candidate for bioengineering and adoptive cellular therapy. Citation Format: Chun Chou, Saida Dadi, Briana G. Nixon, Ming Li. Origin of tumor-elicited cytotoxic innate-like T-cell responses [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A181.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"59 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129812075","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 A218: Modulating glucocorticoid receptor-mediated signaling for enhancement of cancer immunotherapy","authors":"Qin Tang, Myles A. Brown","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A218","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A218","url":null,"abstract":"Glucocorticoids are a class of steroid hormones essential to the modulation of a number of physiologic processes, including cellular metabolism, neural development and immune system function. Functions of glucocorticoids are mediated through the glucocorticoid receptor (GR). Synthetic glucocorticoids are front-line therapies in the clinic for leukemia and lymphoma due to their potent induction of lymphocyte death. Glucocorticoids are also prescribed as adjuvant therapies to chemotherapies to alleviate adverse effects including nausea, emesis and allergic reactions. In the current regimen of immune checkpoint blockade therapies against solid tumors, glucocorticoids are incorporated to manage symptoms related to acute immune hyperactivation. However, given that glucocorticoids preferentially cause lymphocyte death, their inclusion in immune checkpoint blockade regimens which capitalize on cytotoxic T-cell-mediated killing of tumor cells is controversial. The precise effects of systematic glucocorticoids use on tumor development, and particularly, on the tumor-immune microenvironment comprised tumor-infiltrating leukocytes (TILs) remains unknown. Conversely, methods to antagonize glucocorticoid signaling could potentially boost lymphocyte number and function and potentiate cytotoxic T-cell-mediated killing of tumor cells. Presently, the treatment of “immune cold” solid tumor types remains a challenge for immunotherapy due low level of TILs and presence of immunosuppressive cells (including regulatory T-cells and myeloid-derived suppressor cells) in the tumor microenvironment. Pharmacologic modulation of GR presents a unique opportunity to regulate immune cell homeostasis and function with the goal of promoting a favorable tumor immune microenvironment to augment the effectiveness of cancer immunotherapies in solid tumors. Our research seeks to understand the impact of glucocorticoid modulation in the context of immune checkpoint blockade therapies in preclinical models, and to provide a rationale for selective pharmacologic modulation of GR to promote a favorable tumor immune microenvironment and increased efficacy of immunotherapies in solid tumors. We investigated GR activation and inhibition on the immune tumor microenvironment in murine syngeneic melanoma (B16), breast cancer (4T1) and colorectal cancer (CT26) models. Mice bearing allograft tumors were randomized into groups receiving synthetic glucocorticoids or GR inhibitors in combination with anti-PD-1 and anti-CTLA4 therapies. Following treatment, tumors were assessed for composition of intratumoral leukocyte infiltration by flow cytometry phenotyping. In the mouse breast cancer model (4T1), we found evidence supporting substantial lymphodepletion by dexamethasone (a synthetic glucocorticoid compound). Treatment with PD-1 and CTLA-4 blocking monoclonal antibodies increased lymphocyte infiltration into the tumor. Interestingly, immune checkpoint blockade therapies significantly raised the nu","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"277 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124458675","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 PR01: Mechanistic rationale to combine GITR agonism with PD-1 blockade in cancer patients","authors":"R. Zappasodi, C. Sirard, Yanyun Li, S. Budhu, Moshen Abu-Akeel, Cailian Liu, Xia Yang, H. Zhong, W. Newman, Jinjin Qi, P. Wong, David A. Schaer, H. Koon, V. Velcheti, M. Postow, M. Callahan, J. Wolchok, T. Merghoub","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-PR01","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-PR01","url":null,"abstract":"Immune checkpoint blockade has evidenced the therapeutic activity of modulating T-cell co-inhibition/co-stimulation processes. However, many patients are refractory to these therapies, highlighting the need for developing additional forms of immunotherapy targeting alternative immune pathways. In this regard, the T-cell co-stimulatory receptor glucocorticoid-induced TNFR-related protein (GITR, TNFRSF18) is an attractive target for agonist antibodies (Abs). By promoting effector T-cell (Teff) function and hampering regulatory T-cell (Treg) suppression, GITR engagement may exert a dual positive effect on anti-tumor immune responses. We and others have reported potent antitumor effects of anti-GITR Abs in preclinical mouse models. Based on this rationale, we initiated the first-in-human phase-I trial of GITR stimulation with the GITR agonist monoclonal Ab (mAb) TRX518 (NCT01239134). TRX518 is a humanized aglycosylated IgG1κ mAb that binds and stimulates human GITR without engaging Fc effector functions. Here, we report the immune effects of a single ascending dose of TRX518 monotherapy in advanced cancer patients and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. Analysis of peripheral blood mononuclear cells (PBMCs) from 37 advanced refractory solid cancer patients treated with >/= 0.005 mg/kg TRX518 (cohorts 3-9) revealed frequent reductions in circulating Tregs after treatment, with GITR+ Tregs and activated CD45RA-Foxp3hi effector Tregs (eTregs) being preferentially affected. In 8 patients for whom pre- and post-treatment PBMC samples and tumor biopsies were available, reductions in intratumor and circulating Tregs after TRX518 were positively correlated. However, coincident down-regulation of circulating and intratumor Tregs upon TRX518 was not sufficient to achieve a clinical benefit. To clarify the mechanisms underlying this outcome, we modeled tumor sensitivity and refractoriness to anti-GITR therapy by treating B16F10-melanoma-bearing mice with the mAb DTA-1 on day 4 (curative regimen, early tumors) or day 7 (refractory regimen, advanced/established tumors) after tumor implantation respectively. Time course analysis of T-cell infiltrates revealed that intratumor Tregs were significantly reduced and Teff:Treg ratios increased in both responding and refractory tumors. However, in responding tumors, Tregs completely failed to accumulate, suggesting that the presence of Tregs during tumor formation and progression could affect T-cell functionality. Gene expression analysis of intratumor CD8+ T-cells showed up-regulation of activation/memory T-cell markers and down-regulation of exhaustion markers in responding but not in refractory tumors. To overcome resistance to anti-GITR, we thus combined the anti-GITR refractory regimen (day 7 treatment) with PD-1 blockade starting on day 7 after tumor implantation. This combination controlled tumor growth similar to the curat","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"80 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126198459","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 A179: Targeting UCP2 pathway in melanoma cells reprograms the tumor microenvironment and initiates antitumor immune cycle","authors":"Wan-Chen Cheng","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A179","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A179","url":null,"abstract":"Immune checkpoint blockade treatment displays promising therapeutic efficiency in different cancer types. However, a significant proportion of patients are refractory to this treatment due to lack of T-cell infiltration in tumors, a phenotype known as “cold tumors.” To improve the therapeutic benefits of checkpoint blockade, it is crucial to address how to escalate T-cell infiltration into tumors. Here, we characterized melanoma patients in The Cancer Genome Atlas (TCGA) into either high or low T-cell antitumor responses. We then identified the mRNA expression level of mitochondrial uncoupling protein 2 (UCP2) positively correlates with T-cell antitumor immune responses and prolonged patients survival. By using murine melanoma model, we revealed that overexpressing UCP2 in melanoma cells elevates CD8+ T-cell infiltration into the tumor microenvironment (TME) in a conventional type 1 dendritic cell (cDC1)-dependent manner and normalize tumor neovasculature. Mechanistically, UCP2 induction in tumor cells alters the cytokine milieu in tumors and stimulates the recruitment of cDC1 through a IRF5-CXCL10 chemokine axis. Hence, enhancing the expression of UCP2 in melanoma cells provides immunostimulatory shift by engaging the cDC1-CD8+ T-cell dependent antitumor immune cycle in the TME. Interestingly, we demonstrated that inducing UCP2 expression in melanoma cells by genetic approach or administration of rosiglitazone, an approved antidiabetic PPAR agonist, can sensitize PD-1 blockade-resistant melanomas to anti-PD-1 antibody treatment. Accordingly, our data indicate that targeting UCP2 in melanoma cells can be a potent strategy to increase antitumor response to checkpoint blockades in non-T-cell-inflamed tumors. Citation Format: Wan-Chen Cheng. Targeting UCP2 pathway in melanoma cells reprograms the tumor microenvironment and initiates antitumor immune cycle [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A179.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"125005654","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}