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

{"title":"Abstract A197: The HMG transcription factor TOX induces a transcriptional and epigenetic program of CD8+ T-cell exhaustion in chronic infection and cancer","authors":"O. Khan, Josephine R. Giles, Sierra J. McDonald, E. Wherry","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A197","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A197","url":null,"abstract":"The protective capacity of the adaptive immune system relies on efficient and coordinated transitions between cellular fates. Following initial activation by specific antigen, naive CD8+ T-cells proliferate extensively and undergo a highly orchestrated program of molecular rewiring and differentiation into effector CD8+ T-cells (TEFF) that can mediate protection through cytotoxicity and production of inflammatory cytokines. If the infection or antigen is cleared, most of this TEFF pool dies, but a subset persists, undergoing additional differentiation to form a pool of long-lived, self-renewing memory T-cells (TMEM) capable of mounting rapid recall responses. In contrast, during chronic infections or cancer, when T-cell stimulation persists, this program of functional T-cell differentiation is diverted and T-cells fail to sustain robust effector functions, instead becoming exhausted. Exhausted CD8+ T-cells (TEX) may balance limited pathogen or tumor control while restraining damaging immunopathology, but the consequence of restrained functionality is disease persistence and possible progression. Though first described in mice infected with lymphocytic choriomeningitis virus (LCMV), it is now clear that T-cell exhaustion is a common feature of many chronic infections as well as a variety of cancers in both mice and humans. Indeed, TEX are highly therapeutically relevant since these cells are a major target of checkpoint blockade mediated immune reinvigoration in human cancer patients. T-cell exhaustion is characterized by the progressive decline in effector function including the hierarchical loss of inflammatory cytokine production (IL-2, TNFa, IFNg). TEX also sustain high co-expression of multiple inhibitory receptors (PD-1, LAG3, TIGIT, CD160, TIM-3, 2B4), have reduced glycolytic and oxidative phosphorylation capacity, and impaired proliferation and survival. Underlying these major differences in TEX compared to TEFF and TMEM, is a distinct transcriptional program highlighted by altered use of key transcription factors and altered transcriptional circuits. Moreover, recent epigenetic analyses revealed that TEX differ from TEFF and TMEM by ~6,000 open chromatin regions, similar to differences between other major hematopoietic lineages, suggesting that TEX are not simply a state of activation of TEFF or TMEM, but rather are a distinct immune lineage. Yet the mechanisms that initiate this TEX fate commitment and epigenetic and transcriptional programming have thus far remained poorly understood, and exhaustion-specific TFs or transcriptional programming activities have remained elusive. Here we identify the HMG-box protein TOX as a master regulator of the TEX lineage. We find that robust TOX expression is limited to chronic infections and cancers in both mice and humans. TOX is largely dispensable for TEFF and TMEM formation, but in the absence of TOX, TEX do not form. Instead, TOX-deficiency results in the accumulation and subsequent rapid deleti","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"4 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":"128494555","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 A190: Mechanisms governing Foxp3-dependent and -independent gene expression in regulatory T-cells in evolutionary distant mice","authors":"A. Glasner, Y. Zhong, J. V. D. Veeken, A. Rudensky","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A190","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A190","url":null,"abstract":"T regulatory (Treg) cells expressing the forkhead box transcription factor (Foxp3) are important regulators of immunity and play a key role in cancer and metastasis by controlling the activity of effector T-cells. Lineage-specifying transcription factors (TFs) establish cell identity and maintain cell specific transcriptional programs. Foxp3 is a key master TF controlling various Treg cell developmental and functional modalities. Foxp3 deficiency in humans and mice causes a life threatening autoimmune disease, and the enforced expression of Foxp3 in CD4+ T-cells confers suppressor functions. However, our understanding of Treg cell regulation during differentiation in the thymus, and in mature Treg cells in the periphery, whether Foxp3 dependent or independent, is still lacking. Single-nucleotide polymorphism (SNPs) may occur within coding genes or noncoding genomic regulatory areas and can have severe phenotypic consequences. We have recently attempted to link SNPs with differential Treg transcriptomic and epigenetic features in humans. However, such studies are limited by their intrinsic correlative nature, and by the limited number of SNPs. Here we use evolutionally distant mice strains C57Bl/6 (B6), CAST/EiJ (Cast) and SPRET/EiJ (Spret), to identify allele-specific imbalances and functional differences in the transcriptional and epigenetic programs during differentiation and in various conditions of Treg cells and their precursors. Using Foxp3 reporter and conditional knockout (KO) systems combined with interbreeding of the evolutionary distant mice strains in vivo, we explore the genetic and molecular mechanisms of Treg cell differentiation and function, employing high-throughput genomic methods including RNA-seq, ATAC-seq and Chip-seq. Such studies may pave a way for the development of novel therapeutic approaches to treat cancer and metastasis. Citation Format: Ariella Glasner, Yi Zhong, Joris Van Der Veeken, Alexander Rudensky. Mechanisms governing Foxp3-dependent and -independent gene expression in regulatory T-cells in evolutionary distant mice [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 A190.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"22 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":"126597426","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 A206: Extracellular matrix anchoring of locally administered cytokines safely potentiates systemic cancer immunotherapy","authors":"N. Momin","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A206","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A206","url":null,"abstract":"Cytokines coordinate essential mechanisms required for an antitumor response. As a result, they robustly synergize with other immunotherapies. Unfortunately, the clinical use and approval of cytokines is frequently plagued by dose-limiting toxicities. Improving the therapeutic index of cytokines can be achieved by better localizing their effects to the tumor and away from healthy tissue. Recent efforts have shown that local injections of immunomodulatory agents at or around a tumor lesion improve the efficacy and reduce the systemic exposure of these agents. However, even when administered directly into a tumor, cytokines exhibit rapid tumor clearance and limited intratumoral retention, thus doing little to address issues of toxicity and efficacy. Here we demonstrate that extracellular matrix (ECM) anchoring of intratumorally administered cytokines is a facile strategy to retain and confine these agents in the tumor. Although the ECM is an abundant component of both tumors and healthy tissue alike, intratumoral administration obviates the need to target a tumor-specific antigen. Instead, the abundance of matrix lends itself to being an effective and general target for localization across all solid tumors. ECM-anchoring of cytokines via fusion to a matrix-binding protein significantly improves their therapeutic index. Additionally, the combination of ECM-anchored cytokines with a systemic immunotherapy (e.g., a tumor-targeting antibody, checkpoint blockade, a cancer vaccine, or CAR-T-cell therapy) enhances overall survival in syngeneic tumor models compared to combination treatments using unanchored cytokines. Cytokines that are actively retained in the tumor can safely and significantly potentiate systemic immunotherapy. Given the abundant expression of ECM across different cancers, matrix-anchoring of cytokines embodies a tumor-agnostic strategy that can readily be combined with other immunotherapeutic modalities. Citation Format: Noor Momin. Extracellular matrix anchoring of locally administered cytokines safely potentiates systemic cancer immunotherapy [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 A206.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"210 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":"121925573","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 A186: A new strategy to identify and expand tumor-reactive CD8 TILs in human solid tumors","authors":"T. Duhen, Rebekka Duhen, Ryan Montler, T. Moudgil, Jitske van den Bulk, B. Fox, Shu-ching Chang, G. Grunkemeier, E. Verdegaal, N. Miranda, R. Leidner, R. Bell, A. Weinberg","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A186","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A186","url":null,"abstract":"The immune system can recognize and destroy tumor cells through T-cell mediated mechanisms. Hence, identifying tumor antigen-specific T-cells from cancer patients and expanding them in large numbers in vitro has important implications for immunotherapy diagnostics and therapeutics. Here we show that tumor-reactive T-cells are enriched in a subset of tumor-infiltrating CD8 T-cells (CD8 TILs) identified by co-expression of CD103 and CD39 both in primary and metastatic tumors. The CD103+CD39+ CD8 TILs are present at high frequencies in melanoma and mismatch repair-deficient colon cancer but at low frequencies in microsatellite stable (MSS) colon cancer and colorectal liver metastasis. This cell population displays a distinct T-cell receptor (TCR) repertoire, with T-cell clones expanded in the tumor but present at low frequencies in the periphery. Importantly, we show in a MSS colon cancer patient that a very low number of CD103+CD39+ CD8 TILs can be expanded in vitro and that those cells recognize tumor-specific neoantigens. Finally, patients with head and neck cancer whose CD8 TILs contained a higher frequency of CD103+CD39+ cells experienced a greater overall survival. Our work suggests that CD103+CD39+ CD8 TILs are key players in the patient’s antitumor response and describe an approach for detecting and expanding those cells, which will help improve adoptive TIL therapy for cancer patients. Citation Format: Thomas Duhen, Rebekka Duhen, Ryan Montler, Tarsem Moudgil, Jitske van den Bulk, Bernard A. Fox, Shu-Ching Chang, Gary Grunkemeier, Els M.E. Verdegaal, Noel F. de Miranda, Rom Leidner, Richard B. Bell, Andrew D. Weinberg. A new strategy to identify and expand tumor-reactive CD8 TILs in human solid 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 A186.","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":"128055574","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 A180: HHLA2 is a novel tumor-expressed member of the B7 immune checkpoint family","authors":"Jordan M. Chinai, Hao Wang, Xudong Tang, M. Janakiram, Haiying Cheng, X. Zang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A180","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A180","url":null,"abstract":"The purpose of this study was to assess the function and expression-regulation of the new B7 family member, HHLA2, in the tumor microenvironment. HHLA2 is a newly identified B7 family member that has been reported to both inhibit and stimulate T-cell function in vitro. Expression of HHLA2 has been noted on a wide variety of cancers and relatively few normal tissues. The function of HHLA2 in the tumor microenvironment remains elusive and the mechanisms regulating its expression are currently unknown. Challenges to addressing these questions include the lack of a functional HHLA2 gene in mice and, consequently, the lack of in vivo tumor models in which HHLA2 can be studied. Here we assess factors that drive expression of HHLA2 in vivo and present the first humanized mouse model to study the function of HHLA2 expression in the tumor microenvironment. Human cancer cell lines derived from lung, prostate, pancreas, kidney, and colon malignancies were identified with varying levels of HHLA2 expression. HHLA2 surface expression was monitored as these cell lines were grown in vivo as tumors in NSG mice and in vitro under conditions including cytokine stimulation, 3D culture, and hypoxia. Expression was assessed by both flow cytometry and qPCR. HHLA2-knockout cancer cell lines and controls were generated using CRISPR and grown as tumors in NSG mice with human immune cells. These tumors were dissociated and the immune infiltrates were phenotyped by flow cytometry. HHLA2 was upregulated in numerous human cancer cell lines in vivo and expression was reduced or lost in vitro under standard cell culture conditions. Conditions mimicking the tumor microenvironment including 3D culture, hypoxia, and cytokine stimulation all contributed to HHLA2 upregulation. We successfully generated HHLA2-knockout human cancer cell lines and developed a humanized tumor immunotherapy model. HHLA2-expressing tumors contained significantly less infiltrating CD8 and CD4 T-cells than the HHLA2-knockout tumors. The T-cells were also phenotypically less active in the HHLA2-expressing tumors. Expression of HHLA2 in human cancers is driven by environmental conditions that are specific to the tumor microenvironment and this expression appears to have a suppressive effect on infiltrating T-cells. HHLA2 is the newest B7 family member and a promising candidate for targeted immunotherapy against a wide range of cancers. Citation Format: Jordan Manek Chinai, Hao Wang, Xudong Tang, Murali Janakiram, Haiying Cheng, Xingxing Zang. HHLA2 is a novel tumor-expressed member of the B7 immune checkpoint family [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 A180.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"257 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":"134032585","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 A169: Macrophage targeted zoledronic acid conjugated biomineral nanoparticles for γδT-cell-based cancer immunotherapy","authors":"A. Ashokan, M. Anoop, Siju Surendran, Aparna Balakrishnan, Ida M. Anna, A. Ramkumar, Girish Chundayil Madathil, V. Harish, Manzoor Koyakutty","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A169","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A169","url":null,"abstract":"Nanoparticle platforms can be engineered to deliver immune-stimulatory molecules to specific immune cell populations, thereby evoke desired response. Here, we present a novel biomineral nanoparticle system for macrophage specific delivery of bisphosphonate molecules to evoke activation of γδ T-cells for cancer immunotherapy. Generally, γδ T-cells therapy is implemented either by ex vivo expansion followed by adoptive transfer or by in vivo activation using intravenous injection of bisphosphonates. One of the major limitations of intravenously injection of bisphosphonates such as zoledronic acid is its unfavorable biodistribution in the skeletal system due to covalent binding with calcium in the bone. In the present work, we have pre-conjugated zoledronic acid in a calcium-containing biomineral nanoparticle (Zol-BM) that has spontaneous specificity towards macrophages in the liver, spleen and lymph nodes. This enabled targeted expression of γδT-cell stimulating ligand, isopentyl pyrophosphate, in macrophages, leading to enhanced activation of γδT-cells. Optimized Zol-BM showed a drug conjugation efficiency of ~95% with particle size ~ 100 nm and zeta potential, -15mV. The compatibility of Zol-BM was tested in primary human peripheral blood mononuclear cells and macrophages cell lines. The biodistribution analysis of Zol-BM in healthy rat models showed accumulation in liver, spleen and lymph nodes which was confirmed by MRI and Prussian-blue analysis. Flow cytometry based γδT-cell proliferation analysis gave ~18% enhancement in γδ T-cell subset compared to untreated control. Thus, we show that by rational design of engineered nanoparticles, specific immuno-stimulatory molecules like zolendronate can be delivered to desired immune cells of interest (macrophages) for activating another sub-population of immune cells such as γδ T-cells, for cancer-immunotherapy applications. Citation Format: Anusha Ashokan, Minu Anoop, Siju Surendran, Aparna Balakrishnan, Ida M. Anna, Anjana Ramkumar, Girish Chundayil Madathil, Vijay Harish, Manzoor Koyakutty. Macrophage targeted zoledronic acid conjugated biomineral nanoparticles for γδT-cell-based cancer immunotherapy [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 A169.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"205 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":"123260256","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 A200: Targeting ICOS receptor for development of cancer immunotherapy","authors":"Yu-Hsun Lo, Chengpeng Yu, Shu-Han Yu, Tsung-Hang Hseih, M. Chan, Tsai Shih-Chong","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A200","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A200","url":null,"abstract":"Recently, checkpoint blockade-mediated immune reinvigoration acts as potential strategies to cure cancer. In addition to checkpoint blockade, a number of studies have shown that immune co-stimulators also act as crucial players in the immunotherapy. Inducible co-stimulator (ICOS), a homodimeric protein that belongs to CD28 superfamily, is expressed on activated T-cells and resting memory T-cells. Upon stimulation, ICOS and its ligand ICOSL (B7RP-1, B7H-2) have been shown to affect T-cell responses via ICOS-mediated PI3-kinase signaling to enhance the T-cells’ development and activity. In addition, previous studies have shown that ICOS/ICOSL pathway may play an important role in CTLA4 inhibitor-induced tumor immunity. In this study, we aim to develop and implement the Fc-fusion recombinant ICOSL proteins to induce T-cells’ activation for therapeutic use. Our data suggested that recombinant ICOSL-Fc can enhance the proliferation and cytotoxicity effect of human T-cells by increasing INF-γ and IL10 secretion. Moreover, ICOSL-Fc can also inhibit tumor growth in xenograft animal models. Based on our study, ICOS/ICOSL pathway could be a promising therapeutic target for the immunotherapy. Citation Format: Yu-Hsun Lo, Cheng-Chou Yu, Shu-Han Yu, Tsung-Hang Hseih, Mei-Chi Chan, Tsai Shih-Chong. Targeting ICOS receptor for development of cancer immunotherapy [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 A200.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"116 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":"122419521","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 A177: Impact of regulatory T-cells on carcinogenesis of oral squamous cell carcinoma","authors":"Jaime L. Chao, P. Savage","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A177","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A177","url":null,"abstract":"Although some head-and-neck squamous cell carcinomas (HNSCCs) are associated with human papillomavirus (HPV) infection, a large proportion of HNSCCs are HPV-negative and are characterized by mutational signatures associated with smoking, suggesting that HPV-negative HNSCCs are induced by carcinogen exposure. In many human cancers, including HNSCC, regulatory T (Treg) cells are found at elevated densities and are thought to be a major barrier to the generation of robust anti-tumor T-cell responses. However, recent studies indicate that Treg cells can serve diverse functions in non-lymphoid sites. Therefore, it is critical to elucidate the function of Treg cells infiltrating HNSCC lesions. To study the functional impact of Treg cells on the development and progression of HPV-negative HNSCC, we utilized an autochthonous mouse model of carcinogen-induced oral squamous cell carcinoma (SCC), in which mice are exposed long-term to the carcinogen 4-nitroquinoline-1-oxide (4-NQO) in the drinking water. Immunohistochemistry and flow cytometric analysis revealed elevated densities of CD3+ T-cells and Foxp3+ Treg cells in premalignant dysplastic lesions and SCC lesions within the tongue epithelium, suggesting that many lesions exhibit a T-cell-inflamed phenotype. Single-cell TCR sequencing demonstrated the presence of recurrent Treg cell clones within carcinogen-induced lesions, suggesting clonal expansion of Treg cells in the tumor microenvironment. Surprisingly, the systemic depletion of Treg cells at the later stages of carcinogen exposure did not induce tumor regression, but instead induced the opposite effect, driving increased incidence and burden of SCC. These findings suggest that Treg cells may play an unexpected role in restricting the progression of carcinogen-induced SCC in the oral cavity, prompting a re-examination of the common paradigm that Treg cells promote tumorigenesis by suppressing antitumor immunity. Clinically, our findings suggest that novel therapies could be developed to combat HNSCC by triggering the recruitment or activation of tumor-associated Treg cells, and suggest that checkpoint blockade therapies that induce intratumoral Treg cell depletion may have unintended adverse consequences. Citation Format: Jaime L. Chao, Peter A. Savage. Impact of regulatory T-cells on carcinogenesis of oral squamous cell carcinoma [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 A177.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"7 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":"127779562","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 A175: Memory T-cells targeting unique and shared oncogenic mutations detected in peripheral blood of epithelial cancer patients","authors":"G. Cafri, Rami Yossef, A. Pasetto, D. Deniger, J. Gartner, Todd D Prickett, P. Robbins, S. Rosenberg","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A175","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A175","url":null,"abstract":"T-cells targeting shared oncogenic mutations can induce durable tumor regression in epithelial cancer patients. These T-cells can be detected in tumor-infiltrating lymphocytes, but whether such cells can be detected in the peripheral blood of patients with common metastatic epithelial cancer is unknown. Using a highly sensitive in vitro stimulation and enrichment of peripheral memory T-cells from six metastatic cancer patients, we identified and isolated memory T-cells targeting the mutated KRASG12D and KRASG12V variants, in three patients. In an additional two metastatic colon cancer patients, we detected CD8+ neoantigen-specific cells targeting the unique mutated SMAD5 and MUC4 proteins. Therefore, memory T-cells targeting KRAS and neoantigens can be detected in the peripheral blood of epithelial cancer patients and can potentially be used for the development of effective personalized T-cell-based cancer immunotherapy across multiple patients. Citation Format: Gal Cafri, Rami Yossef, Anna Pasetto, Drew Deniger, Jared J. Gartner, Todd Prickett, Paul F. Robbins, Steven A. Rosenberg. Memory T-cells targeting unique and shared oncogenic mutations detected in peripheral blood of epithelial cancer patients [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 A175.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"124 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":"115468976","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 A214: An in vitro preclinical package to assess the safety and efficacy of ImmTAC™ molecules","authors":"Ana Ribeiro, Tomasz Dobrzycki, Jane V. Harper, G. Bossi, D. Wright, Andrea R. Stacey, N. Bedke, R. Martinez-Hague, D. Blat, L. Humbert, Z. Donellan, S. Paston, L. Weigand, M. Canestraro, Sophie Botta Gordon-smith, B. Jakobsen, J. Dukes","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A214","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A214","url":null,"abstract":"Immune Mobilising Monoclonal TCRs Against Cancer (ImmTAC) molecules are a new class of bi-specific biologic specifically designed to recognize and eradicate cancer cells. ImmTAC molecules are composed of an affinity-enhanced T-cell receptor (TCR) fused to an anti-CD3 effector function engineered to recognize peptides presented by human leukocyte antigen (HLA) and induce T-cell activation and T-cell mediated killing of tumor cells. TCR-based immunotherapeutic strategies offer distinct advantages over traditional antibody-based therapies, most notably providing access to up to nine-fold more cancer targets by targeting intracellularly processed peptides presented by HLA as opposed to cell surface proteins. Preclinical testing of ImmTAC molecules can prove particularly challenging as these molecules are exquisitely human-specific, requiring a human peptidome and intact human immune system; thus the use of conventional animal models is inappropriate. Given that these molecules harness the full force of the immune system, robust preclinical testing is essential to predict safety and efficacy and inform on clinical dosing for first-in-human studies. Here we present, to our knowledge, the first entirely in vitro preclinical package that comprises a range of cellular and molecular assays to assess the efficacy, safety and specificity of ImmTAC molecules. To exemplify our approach, we draw upon the preclinical testing of multiple ImmTAC molecules, including IMCgp100, the first ImmTAC molecule to reach the clinic. We propose that this preclinical package can be applied to the testing of other TCR-based therapies to deliver a more physiologically relevant model. Citation Format: Ana Ribeiro, Tomasz Dobrzycki, Jane Harper, Giovanna Bossi, Debbie Wright, Andrea Stacey, Nicole Bedke, Ruth Martinez-Hague, Dan Blat, Laure Humbert, Zoe Donellan, Samantha Paston, Luise Weigand, Martina Canestraro, Sophie Botta Gordon-Smith, Bent K. Jakobsen, Joseph Dukes. An in vitro preclinical package to assess the safety and efficacy of ImmTAC™ molecules [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 A214.","PeriodicalId":170885,"journal":{"name":"Regulating T-cells and Their Response to Cancer","volume":"22 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":"130552927","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}