Investigating the Interplay between Senescent Cells and T Cells in Cancer

研究癌症中衰老细胞和 T 细胞之间的相互作用

• 批准号: 10662221
• 负责人: Caroline Broderick
• 金额: $ 4.77万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662221
• 关键词: Biology; Bypass; CRISPR screen; Cell Aging; Cell Communication; Cell Compartmentation; Cell Cycle Arrest; Cell secretion; Cells; Cellular Stress; Chronic; Clinical; DNA Damage; Data; Funding; Gene Expression Profile; Genes; Goals; Growth; Immune; Immunologic Stimulation; Immunologic Surveillance; In Vitro; Inflammation; Inflammatory; Learning; Malignant Neoplasms; Mediating; Oncogenes; Pharmaceutical Preparations; Phenotype; Predisposition; Proliferating; Relapse; Research; Resistance; T cell infiltration; T-Lymphocyte; Telomere Shortening; Therapeutic; Training; Tumor Immunity; Tumor Promotion; Tumor Suppressor Proteins; Tumorigenicity; Validation; anti-tumor immune response; anticancer research; cancer infiltrating T cells; cancer therapy; candidate validation; carcinogenesis; cell killing; chemokine; cytokine; improved; in vivo; liver cancer model; mouse model; neoplastic cell; novel; programs; recruit; resistance mechanism; response; restoration; senescence; success; therapy resistant; tumor; tumor immunology; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

Project Summary/Abstract Cellular senescence is considered a “double-edged sword” in cancer and cancer therapy – while senescence- associated growth arrest and immune stimulation serve as potent anti-tumor mechanisms, chronic inflammation can be pro-tumorigenic and senescence bypass can contribute to therapy resistance and relapse. Many clinically used cancer therapies have been shown to trigger cellular senescence in tumor cells, so understanding the effects of senescent cells on the tumor microenvironment is critical. Gaining a clear understanding of the mechanism of senescence-inducing therapies will enable their improved clinical use and increase the likelihood for their success as cancer therapeutics. There is considerable evidence that senescent cells are proinflammatory and can be surveilled by T cells in vivo. This proposal will dissect the interplay between senescent cells and T cells in a mouse model of Hepatocellular Carcinoma in which senescence-induced T cell-mediated tumor regressions have been observed. Aim 1. Investigate senescence-induced T cell surveillance of senescent and proliferating tumor cells. I hypothesize that senescent tumor cells secrete chemokines that promote T cell infiltration and surveillance of both senescent and proliferating tumor cells. Aim 2. Identify strategies to potentiate T cell surveillance of senescent tumor cells. I hypothesize that senescent tumor cells employ resistance programs that diminish T cell recognition or killing. Validation of the hypotheses set forth in this proposal would have major implications in the fields of senescence biology and tumor immunology, as well as for the use of senescence-inducing therapies as clinical cancer therapeutics.

项目摘要/摘要 细胞感应被认为是癌症和癌症治疗中的“双刃剑” - 而感应 - 相关的生长停滞和免疫刺激是潜在的抗肿瘤机制，慢性 炎症可以是促肿瘤的，感应旁路可以导致耐药性和缓解。 许多临床使用的癌症疗法已被证明会触发肿瘤细胞中的细胞感应，因此 了解感觉细胞对肿瘤微环境的影响至关重要。获得清晰 了解感应诱导疗法的机制将使它们改善临床使用和 增加了作为癌症治疗成功的可能性。 有大量证据表明，感觉细胞是促炎性的，可以由T细胞在 体内。该建议将在小鼠模型中剖析感觉细胞和T细胞之间的相互作用 肝细胞癌感应诱导的T细胞介导的肿瘤回归已经是 观察到。 AIM 1。研究感官诱导的T细胞监测的感觉和增殖肿瘤细胞。我 假设感觉肿瘤细胞的秘密趋化因子促进T细胞浸润和监视 感觉和增殖的肿瘤细胞。 目标2。确定策略以潜在的T细胞监测感肿瘤细胞。我假设这一点 感觉肿瘤细胞的员工抵抗程序会减少T细胞识别或杀伤。 验证本提案中提出的假设将在该领域具有重大影响 衰老生物学和肿瘤免疫学，以及使用感应诱导的疗法作为临床 癌症治疗学。