Functional Activation of Low Affinity TILs

低亲和力 TIL 的功能激活

• 批准号: 10055781
• 负责人: Jill E Slansky
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-03 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055781
• 关键词: Address; Affinity; Agonist; Antigens; Autoantigens; Automobile Driving; Biochemical; Biological Assay; Blocking Antibodies; Cells; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colorectal; Colorectal Cancer; Country; Data; Development; Epigenetic Process; Frequencies; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic; Genetic Transcription; Goals; Human; ITIM; Immune system; Immunotherapy; Integral Membrane Protein; Knowledge; Laboratories; Lead; Life; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Methods; Mission; Modeling; Molecular; Molecular Target; Mus; Mutation; Nucleic Acid Regulatory Sequences; Pathway interactions; Peptides; Pharmacotherapy; Property; Proteins; Public Health; Reaction; Regulatory Pathway; Research; Research Personnel; Resolution; Sampling; System; T cell response; T-Cell Development; T-Lymphocyte; Techniques; Technology; Testing; Thymus Gland; Toxic effect; Transgenic Animals; Translating; Transposase; Tumor Antigens; Tumor Immunity; Tumor-Infiltrating Lymphocytes; United States National Institutes of Health; anti-CTLA4; cancer immunotherapy; cancer therapy; central tolerance; checkpoint receptors; combat; cytotoxic; epigenome; experience; immune checkpoint blockade; improved; innovation; interest; multimodality; neoantigens; neoplastic cell; new therapeutic target; novel; novel therapeutic intervention; programmed cell death protein 1; programs; receptor; response; src Homology Region 2 Domain; tool; transcriptome sequencing; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT There is a fundamental gap in understanding how to activate and increase tumoricidal activity low-affinity tumor infiltrating lymphocytes (TILs) that recognize antigens derived from dysregulated unmutated proteins. Continued existence of this gap represents an important problem because there are many tumors with a low mutation load that do not respond to current treatments, but elicit low-affinity T cell responses. Our long-term goal is to identify unique inhibitory receptors that are functionally enriched in TILs and epigenetic targets to help establish mechanisms that contribute to development of future therapies for these cancers. The overarching goal of this research is to elucidate pathways that can be harnessed to improve antitumor T cell activity, particularly the activity of low-affinity TILs. The central hypothesis is that the antitumor activity of low- affinity T cells is sensitive to enhancement by blocking inhibitory receptors and targeting epigenetic regulatory regions. This hypothesis has been formulated on the basis of preliminary data produced in the applicants' laboratories. The rationale for the proposed research is that understanding the activation and differentiation of low-affinity T cells has the potential to translate into better understanding of better therapies for cancer that now afflicts one of every two to three people in this country. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Establish mechanisms that modulate antitumor activity of low- affinity TILs by defining their inhibitory receptor repertoire, and 2) Establish mechanisms of epigenetic programming in low-affinity TILs. Both of these aims will use retrogenic technology to generate large pools of either high or low-affinity tumor-specific T cells. In the first aim, inhibitory receptors will be identified from a list of ITIM-containing genes that were found by the investigators to be upregulated in TILs and using biochemical approaches that identifies inhibitory receptors from low-affinity T cells using SH2 domains. The genes of interest identified in this aim will be confirmed in other systems and probed on human colorectal samples to determine their expression on human TILs. In the second aim, gene expression and chromatin accessibility of low and high affinity T cells in the periphery and tumor will be examined. The effects of T cells development in tumor antigen-deficient mice will also be examined. The approach is innovative, in the applicant's opinion, because it departs from the status quo of looking at the highest affinity reactions against tumors using novel methods. The contribution of the proposed research will be significant because identification of inhibitory receptors and epigenetic targets expected to activate endogenous low-affinity T cells may have fewer toxicities and activate T cells in some tumors that have not yet experienced the benefits of immunotherapies. Ultimately, such knowledge has the potential to inform the development of immunotherapies for cancers that do not as yet have treatments.

项目摘要/摘要 在理解如何激活和增加杀肿瘤活性方面存在根本性的差距。 浸润性淋巴细胞（TIL），其识别来自失调的未突变蛋白的抗原。 这种差距的持续存在代表了一个重要的问题，因为有许多肿瘤具有低的 突变负荷，不响应当前的治疗，但引发低亲和力T细胞反应。我们的长期 我们的目标是鉴定功能上富集在TIL和表观遗传靶点中的独特抑制性受体， 帮助建立有助于开发这些癌症未来疗法的机制。的 这项研究的首要目标是阐明可以利用来改善抗肿瘤T细胞的途径， 活性，特别是低亲和力TIL的活性。中心假设是，低- 亲和力T细胞通过阻断抑制性受体和靶向表观遗传调节因子而对增强敏感。 地区这一假设是根据申请人在申请书中提出的初步数据提出的。 laboratories.这项研究的基本原理是，了解细胞的激活和分化， 低亲和力T细胞有可能转化为更好地理解癌症的更好疗法， 现在困扰着这个国家每两到三个人中的一个。在强有力的初步数据的指导下， 将通过追求两个具体目标进行测试：1）建立调节低- 通过定义它们的抑制性受体库，和2）建立表观遗传学的机制， 在低亲和性TILs中编程。这两个目标都将使用转基因技术来产生大量的 高或低亲和力肿瘤特异性T细胞。在第一个目标中，将从列表中识别抑制性受体。 研究人员发现，ITIM基因在TIL中上调， 使用SH 2结构域从低亲和力T细胞中鉴定抑制性受体的方法。的基因 将在其它系统中确认在该目的中鉴定的兴趣，并在人结肠直肠样品上探测， 确定它们在人TIL上的表达。在第二个目标中，基因表达和染色质可及性， 将检查外周和肿瘤中的低和高亲和力T细胞。T细胞发育在 还将检查肿瘤抗原缺陷小鼠。申请人认为，这种方法是创新的， 因为它偏离了使用新的抗体来观察针对肿瘤的最高亲和力反应的现状， 方法.该研究的贡献将是显著的，因为抑制性的鉴定 预期激活内源性低亲和力T细胞的受体和表观遗传靶点可能具有更少的毒性 并激活一些尚未经历免疫疗法益处的肿瘤中的T细胞。最后， 这些知识有可能为癌症免疫疗法的发展提供信息， 接受治疗