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

{"title":"Abstract A201: Single-cell resolution profiling of tumor-reactive CD4 T-cells reveals immune landscape alterations","authors":"Assaf Magen, J. Nie, T. Ciucci, Yongmei Zhao, M. Mehta, Bao Tran, S. Hannenhalli, R. Bosselut","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A201","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A201","url":null,"abstract":"T-cell responses to tumors are typically neutralized through a variety of mechanisms. While cytotoxic CD8 cells have been the focus of most efforts to exploit T-cell responses against tumors, recent studies have demonstrated the clinical potential of the CD4 tumor-infiltrating lymphocytes (TILs). However, the functional diversity characteristic of these cells has limited our ability to harness CD4 TILs to fight tumors. To address this issue, we have used new experimental strategies to characterize the heterogeneity of the antitumor CD4 response in vivo, combining (i) tracking of CD4 T-cells specific for a defined recombinant tumor antigen, both in the tumor microenvironment and draining lymph node (dLN), (ii) genome-wide mRNA sequencing at the single-cell level (scRNAseq) and (iii) new computational approaches to increase the resolution of subpopulations discovery and uncover robust transcriptional changes across populations. We find novel subpopulations of regulatory (Treg) and effector (Th1) TILs expressing diverse co-inhibitory gene programs unique to the tumor microenvironment. In contrast to TILs composition, we find an unexpected Follicular helper (Tfh)-like cells and non-classical Th1 response in dLN. Comparison of TIL subpopulations to those defined in an immune response to viral infection (LCMV) reveals gene expression patterns unique to cancer. Our study uncovers previously unknown CD4 T-cell effector programs that provide ineffective responses and fail to control tumor progression. Targeting these programs should provide new options for the design of improved immunotherapy strategies. Citation Format: Assaf Magen, Jia Nie, Thomas Ciucci, Yongmei Zhao, Monika Mehta, Bao Tran, Sridhar Hannenhalli, Remy Bosselut. Single-cell resolution profiling of tumor-reactive CD4 T-cells reveals immune landscape alterations [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 A201.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"6 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":"133380327","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 A222: Exploiting mTORC1-independent protein synthesis in Tregs to boost antitumor immune response","authors":"Viviana Volta, Amanda W Ernlund, C. Parra, Abilash Gadi, Amanda Valeta-Magara, R. Schneider","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A222","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A222","url":null,"abstract":"Regulatory T-cells (Tregs) maintain immune system homeostasis in the organism. In the tumor micro-environment, however, Tregs can hinder antitumor immune response. Treg maturation in peripheral sites (pTregs) requires inhibition of protein kinase mTORC1, which paradoxically blocks mRNA translation. mTORC1 phosphorylates (inactivates) 4E-BP1, a negative regulator of the translation initiation factor eIF4E. When mTORC1 is active, 4E-BP1 is hyperphosphorylated and releases eIF4E, which can then bind the mRNA cap structure and promote eIF4F complex assembly and ribosome recruitment. Inhibition of mTORC1 results in hypo-phosphorylation (activation) of 4E-BP1, which then binds and sequesters eIF4E, preventing its interaction with the cap and ribosome association to the mRNA. Using human CD4+ T-cells differentiated in vitro, we show that mTORC1 inhibition strongly impairs protein synthesis, yet with exposure to TGFbeta, is essential to mediate iTreg differentiation and immune suppression activity. We found that TGFbeta reprograms the T-cell transcriptome, while mTORC1 inhibition reprograms the translatome (genome-wide translation signature), mediating Treg differentiation. Genome-wide transcription and translation profiling identified TGFbeta-upregulated mRNAs resistant to mTORC1 inhibition, in part due to their 5’-untranslated regions, that induces Treg differentiation and immune suppression activity. These include canonical pTreg fate-determining mRNAs FOXP3, CTLA-4, CD101 and CD103, among others. Inhibition of mTORC1 alone or TGFbeta alone induces iTregs with poor immune suppression activity. Treg differentiation is therefore mediated by an mTORC1-independent privileged mRNA translation mechanism that converts activated CD4+ T-cells to Tregs. These findings are quite relevant in the tumor microenvironment, where mTORC1-inhibiting conditions such as hypoxia and deprivation of nutrients and energy are present. Investigation of molecular targets acting in this mTORC1/eIF4E-independent translation of Treg mRNAs is ongoing. These targets could be drugged to selectively inhibit Treg differentiation in the tumor microenvironment, thus allowing effector cells to mount the response against cancer cells. Citation Format: Viviana Volta, Amanda Ernlund, Columba De la Parra, Abilash Gadi, Amanda Valeta-Magara, Robert J. Schneider. Exploiting mTORC1-independent protein synthesis in Tregs to boost antitumor immune response [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 A222.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"2016 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":"114731709","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 A191: Novel approaches to the study of NK cell exhaustion in humans","authors":"E. González-Gugel, Keerthi Caroline Sadanala, Adeeb H. Rahman, R. Blumberg, A. Horowitz, N. Bhardwaj","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A191","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A191","url":null,"abstract":"The engagement of activating or inhibitory receptors and production of immunosuppressive factors in the tumor microenvironment can modulate NK cell activities, such as cytotoxicity and cytokine production. In certain instances, NK cells acquire a dysfunctional state, resembling the “exhaustion phenotype” described for T-cells characterized by (i) overexpression of inhibitory receptors such as PD-1, CTLA-4, LAG-3, TIGIT and TIM-3, (ii) down regulation of cytokine receptors, rendering them refractory to cytokine stimulation; (iii) loss of function (cytotoxicity, abnormally low cytokine production, and proliferation); and (iv) down regulation of transcription factors T-bet and Eomes. The mechanisms underlying NK cell exhaustion in cancer remain undefined. We hypothesized that the interaction between immunogenetics, education and environment may play an important role during induction of NK cell exhaustion. Checkpoint molecules and NK cell receptors such as Tim-3, TIGIT, inhibitory KIRs and NKG2A among others are key candidates for mediating the exhaustion profile. The aim of this project was to use a selected collection of healthy donors who are HLA and KIR genotyped, and whose CMV and EBV status are defined, to i) clarify the steady state distribution of checkpoint molecules on NK cells between individuals and ii) determine how these profiles change with exposure to immune suppressive environments. In order to do so we applied Mass Cytometry (CyTOF) technology for detailed analysis. In addition, we developed an in vitro NK cell exhaustion assay used to evaluate gradual changes in NK cell activity determined by their cytotoxicity and cytokine production capacities. Purified NK cells from healthy individuals were cultured for short- and long-term cultures with completed media supplemented with recombinant human (rh)-IL-2 or rhIL-15 in the presence of increasing TGF-β concentrations (from 0.05, 0.5, 5 to 50ng/ml); or co-culture with m44, Gmel and Skm147 melanoma cell lines at a ratio of 1:10. Analysis of NK cell dysfunction was determined by quantifying degranulation and IFN-γ production. Our preliminary results confirmed that both immunosuppressive factors and NK cell ligands from the tumor microenvironment are necessary to completely shut down NK cell function. Interactions between NK cell ligands and their specific NK cell receptors are crucial for the induction of NK cell exhaustion in vitro by reducing NK cell activity nearly 80% measured by degranulation and IFN-γ production, whereas addition of increasing concentrations of rhTGF-β1 into the culture gradually drives NK cells to a process of exhaustion by reducing their cytotoxicity and cytokine production capacities by 40-50%. TGF-β1 immunosuppressive effect on NK cells reaches a maximum at 6 days of in vitro culture by noncanonical TGF-β signaling. More than that, we are able to confirm differences in the expression of activating or inhibitory NK cell receptors presented by each individual base","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"62 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":"129478889","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 A223: CD36-mediated metabolic adaptation guides regulatory T-cells in tumors","authors":"Haiping Wang, Ping-Chih Ho","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A223","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A223","url":null,"abstract":"Regulatory T-cells (Tregs) play an indispensable role in maintaining peripheral tolerance and preventing autoimmune disease. In addition to modulating tissue homeostasis, the suppressive properties of Tregs can also be harnessed by cancers to evade immunosurveillance. Therefore, depleting Tregs has been shown to unleash antitumor immunity and interrupt formation of an immunosuppressive tumor microenvironment (TME). However, systemic loss of Tregs due to Treg depletion also leads to severe autoimmunity. Therefore, the identification of novel approaches that specifically target intratumoral Tregs is direly needed for unleashing antitumor immunity and cancer immunotherapy. Here we show that intratumoral Tregs increase lipid uptake and content and elevated expression of CD36, a fatty acid translocase, as compared to Tregs in circulation and other normal tissues, in several cancer types. By using the transgenic mice model, we found that Treg-specific ablation of CD36 reduces accumulation of intratumoral Treg and suppresses tumor growth. Importantly, Treg-specific CD36 deficiency does not lead to autoimmunity in aged mice and CD36-deficient Tregs remain their suppressive activity on restraining CD4 T-cell-induced inflammatory bowl disease. Mechanistically, CD36 expression supports survival of intratumoral Tregs by fine-tuning their mitochondrial fitness via PPAR signaling. Thus, high expression of CD36 in intratumoral Tregs orchestrates Treg metabolic adaptation in tumors by intervening metabolic regulations, and further promotes tumor growth by suppressing the antitumor immune responses. Ultimately, anti-PD-1 blockade treatment elicits therapeutic benefits in mice with Treg-specific ablation of CD36. Altogether, our study suggests that CD36 might be a potential target for specifically waning down intratumoral Tregs and provide proof-of-concept evidence that targeting CD36 in tumors could unleash antitumor immunity and synergize with checkpoint blockade treatment. Citation Format: Haiping Wang, Ping-Chih Ho. CD36-mediated metabolic adaptation guides regulatory T-cells in tumors [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 A223.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"25 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":"127545472","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 A217: TCR affinity determines the fate of T-cells in tumors","authors":"M. Shakiba","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A217","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A217","url":null,"abstract":"T-cell-mediated immune responses are triggered by T-cell receptor (TCR) binding to peptide-major histocompatibility complex (pMHC). In acute infections, affinity of TCR:pMHC interaction is a critical determinant of T-cell expansion and effector function. However, little is known about how tumor (neo) antigen affinity impacts T-cell differentiation and dysfunction in tumors. To investigate the functional and molecular programs determined by affinity, we generated an in vivo tumor model expressing altered peptide ligands (APL) derived from a native tumor neoantigen recognized by antigen-specific CD8 T-cells with varying functional avidity. While affinity did not impact T-cell activation in tumor draining lymph nodes, it drove distinct functional and molecular pathways at the tumor site: key transcription factors and effector molecules were regulated by signal strength, preserving a cell-intrinsic functional program in T-cells with lower-affinity interactions, while certain hallmarks of T-cell dysfunction, including the expression of some inhibitory receptors, were affinity-independent. RNAseq and ATACseq analyses revealed distinct affinity-dependent transcriptional and epigenetic programs in low- vs. high-affinity T-cells that drive their functional differences. Together these results reveal that TCR:pMHC affinity plays a critical role in defining the epigenetic and transcriptional states and ultimately fate of tumor-specific T-cells. Citation Format: Mojdeh Shakiba. TCR affinity determines the fate of T-cells in tumors [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 A217.","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":"130128251","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 A176: Overcoming CD8 T-cell suppression in the tumor microenvironment","authors":"Adam N. Cartwright, Peng Jiang, A. Saadatpour, Guocheng Yuan, Shirley X. Liu, K. Wucherpfennig","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A176","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A176","url":null,"abstract":"CD8 T-cell-mediated antitumor immunity is required for the control and elimination of tumors. However, tumors are able to overcome immune response resulting in immunosuppression, tumor growth, and metastatic spread. CD8 T-cells are controlled through a homeostatic network of positive and negative feedback loops. These negative signals are exploited by the tumor and associated suppressive cell populations in the tumor microenvironment. Immunotherapies targeted to receptors that control these negative signals, termed immune checkpoint inhibitors, have provided robust and durable responses to a number of cancers. Unfortunately, only a subset of patients will respond to current immunotherapies. This is due to the accruement of suppressive and inhibitory mechanisms employed by the tumor and its microenvironment. These include expression of inhibitory ligands, release of immune-suppressive factors, and the recruitment of suppressive cell populations. Furthermore, the administration of immune checkpoint inhibitors can enhance tumor acquisition of a more suppressive phenotype, diminishing immune responses through additional inhibitory pathways. We therefore propose that further CD8 T-cell-intrinsic negative regulators most likely exist, which can be targeted to improve antitumor responses. Here, we have used functional genomic approaches to identify pathways that can be targeted to advance anti-tumor responses, either in combination with anti-PD-1 or to overcome suppressive mechanisms employed by the tumor microenvironment. Using both in vivo and in vitro assays, we have identified both a novel target that provides an enhancement to CD8 T-cell effector function when in combination with PD-1 checkpoint blockade, and CD8 T-cell-intrinsic pathways that are modulated by the presence of suppressive cells associated with the tumor microenvironment. Citation Format: Adam N.R Cartwright, Peng Jiang, Assieh Saadatpour, Guo-Cheng Yuan, Shirley X. Liu, Kai W. Wucherpfennig. Overcoming CD8 T-cell suppression in the tumor microenvironment [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 A176.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"29 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":"130792552","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 A212: Expanded CD8+PD-1+ T-cell and TCR repertoire signatured clinical response of adoptive T-cell immunotherapy in advanced pancreatic cancers","authors":"G. Qiao","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A212","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A212","url":null,"abstract":"Purpose: Advanced pancreatic cancer(APC) has remained challenging to treat effectively. This study aimed to explore the biologic antitumor activities of sorted CD8+PD-1+T-cells expanded from peripheral blood mononuclear cells (PBMCs) and analyze the prognostic values of fold expansion capacity of functional CD8+PD-1+T-cells and TCR repertoire after ex vivo expansion. Experimental Design: 25 selected APC patients who had been previously confirmed with improved clinical response based on chemotherapeutic S-1 plus adoptive T-cell immunotherapy were further stratified to identify the biologically molecular mechanism of expanded CD8+PD-1+T-cell and restored TCR repertoire on post-infused patients’ peripheral blood T lymphocytes phenotype and subsequent association with clinical responses. Results: The harvested PMBCs were expanded ex vivo under the cytokines’ stimulation. The induced CD3+, CD3+CD4+, CD3+CD8+T-cells components reached the peak value in 15 days. CD8+T-cells exhibited enhanced expression of PD-1, LAG-3, and TIM-3 after ex vivo expansion except for 4-1BB. Survival analysis showed that patients with ratio of post/pre CD8+PD-1+T-cells more than 2 had significantly favorable overall survival (OS) (median OS time 238 days versus 142 days, P=0.024) and progressive-free survival (PFS) (median PFS time 180 days vs 85 days, P=0.002). The sorted CD8+PD-1+T-cells were featured by enhanced antitumor activities with the appearance of increased release of IFN-γ secretion and up-regulation of 4-1BB after co-culture with autologous tumor cell line. TCR repertoire diversity simultaneously rose during the ex vivo expansion in which increased unique clones could result in peripheral blood immunologically phenotypic improvements represented by CD8+ enhancement and CD8+/CD28- decline. Moreover, TCR increased unique clones were associated with significantly favorable OS (median OS time 216 days versus 112 days, P=0.031) and PFS (median PFS time 166 days vs 79 days, P=0.043) and the alteration of CD8+PD-1+T-cells (r2=0.464, P=0.001). Conclusion: This study showed that CD8+PD-1+T-cells after ex vivo expansion in 15 days could be identified as the tumor-reactive cells. The present discoveries were filled with that expanded CD8+PD-1+T-cells and restored TCR repertoire were significantly associated with clinical responses in APC. Citation Format: Guoliang Qiao. Expanded CD8+PD-1+ T-cell and TCR repertoire signatured clinical response of adoptive T-cell immunotherapy in advanced pancreatic cancers [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 A212.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"33 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":"133471232","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 A167: Prevalence of TREG cells and effects of their inhibition on growth of oral cancer cells","authors":"S. Aggarwal, Suresh C. Sharma, Satya N. Das","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A167","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A167","url":null,"abstract":"Oral squamous cell carcinoma (OSCC) is one of the major cancers affecting Asian countries. The main causative factor has been tobacco habit. It has been reported that immune dysfunction in these patients is one of the major factors for tumor growth and dissemination that affects disease-free survival of the patients. We assessed the phenotypic and functional characteristics of regulatory T (Treg) CD4+CD25+FoxP3+subsets in patients with OSCC by multicoloured flow cytometry. Subsequently we investigated the effects their inhibition via TDG on growth of OSCC cell lines in vitro. An increased (p Citation Format: Sadhna Aggarwal, Suresh C. Sharma, Satya N. Das. Prevalence of TREG cells and effects of their inhibition on growth of oral cancer cells [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 A167.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"20 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":"131130921","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 A166: Reprogramming of exhausted T-cells following cure of chronic viral infection","authors":"Mohamed S. Abdel-Hakeem, Jean-Christophe Beltra, Zeyu Chen, John L. Johnson, S. Manne, Mohammed-Alkhatim A. Ali, E. Wherry","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A166","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A166","url":null,"abstract":"T-cell exhaustion is a hallmark of immunologic failure in chronic infections and cancer. Blocking immune inhibitory receptors such as programmed death-1 (PD-1) can re-invigorate exhausted T-cells (Tex), but many patients fail to achieve durable disease control. Thus, a deeper understanding of molecular pathways underlying reversal of T-cell exhaustion is needed. Little is known about “reprogramming” of Tex into recovered T-cells (Trecov) with better functionality and durable memory properties following cure of chronic disease. Here, we aim to determine the molecular program and underlying mechanisms of Trecov. We used the well-defined LCMV mouse model of T-cell exhaustion. To achieve “cure” of chronic infection, we adoptively transferred Tex from mice chronically infected with LCMV clone 13 into antigen-free mice and interrogated changes in Tex as they recovered, including testing the recall capacity of Trecov, a quintessential memory T-cell (Tmem) property. These studies revealed some recovery of phenotypic markers of T-cell memory, but also demonstrated that “scars” of chronic infection persisted. For example, although expression of the IL-7R was increased and PD-1 expression was lower, consistent with differentiation toward memory, the frequency of IL-7R+ cells was lower and PD-1 expression was still higher when compared to bona fide memory T-cells. These changes were accompanied by partial recovery from dysfunction, where Trecov displayed a moderate improvement in effector function. Consistent with this partial recovery, single-cell RNA sequencing (scRNAseq) indicated that the gene-expression profile of Trecov resembles Tmem in some respects, but other features were still more similar to Tex cells. To test how this collection of changes impacted a key property of Tmem, the ability to mount a recall response, we designed a series of challenge experiments. These studies revealed that although Trecov responded better than Tex, recall capacity was still inferior on a per cell basis compared to true Tmem. Together, these results suggest that following elimination of persistent antigenic stimulation and inflammation, previously exhausted T-cells are able to recover some properties of Tmem, while other aspects remain “scarred” from their history of exhaustion. These studies will enhance our understanding of immunologic and molecular mechanisms of Tex recovery, and have the potential to identify novel therapeutic strategies for recovery of more durable functional T-cells in the treatment of cancer and chronic infection. Citation Format: Mohamed S. Abdel-Hakeem, Jean-Christophe Beltra, Zeyu Chen, John Johnson, Saskinath Manne, Mohammed-Alkhatim Ali, E. John Wherry. Reprogramming of exhausted T-cells following cure of chronic viral infection [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 Immu","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"35 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":"132821990","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 A203: Role of nonimmune functions of regulatory T-cells in inflammation and tissue homeostasis","authors":"A. Mendoza","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A203","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A203","url":null,"abstract":"Regulatory T-cells (Treg) are a T-cell lineage vital to promoting tolerance to self antigens, commensal bacteria, and environmental antigens, as well as limiting responses to acute and chronic infections. Because of their critical role in immunosuppression in diverse biologic settings—including the tumor microenvironment—therapeutic targeting of Treg cells holds promise for cancer immunotherapy. In addition to dampening immune responses against tumor antigens and the associated inflammation, tissue-resident Treg cells may directly support tumor growth, homeostasis, and metastasis. Hence, understanding Treg cell functions independent from immunomodulation may provide novel targets for cancer therapy without the adverse side effects associated with immune checkpoint blockade. Studies of Treg cells found in non-lymphoid tissues have revealed transcriptional signatures and functions distinguishable from those found in Treg cells residing in secondary lymphoid organs, suggesting that Treg cells may perform a variety of specialized functions within non-lymphoid tissues. In addition, Treg cells can show distinct localization within non-lymphoid organs, raising the possibility that they may interact with different immune and non-immune tissue resident cells. In particular, we find frequent Treg cell localization in close proximity to peripheral neurons. Gene expression analysis has revealed expression of neuromodulatory molecules by Treg cells, further suggesting interplay between Treg cells and peripheral neurons. Interactions between Treg cells and the peripheral nervous system may play an important role in limiting immune responses and/or promoting tissue homeostasis. Understanding potential neuromodulatory activity of Treg cells and its effect on inflammation, tissue homeostasis and cancer could reveal novel strategies for therapeutic possibilities. Citation Format: Alejandra Mendoza. Role of nonimmune functions of regulatory T-cells in inflammation and tissue homeostasis [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 A203.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"23 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":"133722079","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}