Investigating the Interplay between Senescent Cells and T Cells in Cancer

项目总结/摘要 细胞衰老被认为是癌症和癌症治疗中的“双刃剑”-而衰老- 相关的生长停滞和免疫刺激作为有效的抗肿瘤机制， 炎症可能是促肿瘤发生，衰老旁路可能导致治疗抗性和复发。 许多临床使用的癌症疗法已被证明会引发肿瘤细胞的细胞衰老， 了解衰老细胞对肿瘤微环境的影响至关重要。获得明确的 对衰老诱导疗法的机制的理解将使其能够改善临床应用， 增加它们作为癌症治疗剂成功的可能性。 有相当多的证据表明，衰老细胞是促炎性的，并且可以被T细胞监视， vivo.这项建议将剖析衰老细胞和T细胞之间的相互作用，在小鼠模型， 肝细胞癌中衰老诱导的T细胞介导的肿瘤消退已被 观察 目标1.研究衰老诱导的T细胞对衰老和增殖肿瘤细胞的监视。我 假设衰老肿瘤细胞分泌促进T细胞浸润和监视 衰老和增殖的肿瘤细胞。 目标2.确定加强衰老肿瘤细胞的T细胞监视的策略。我假设 衰老的肿瘤细胞采用减少T细胞识别或杀伤的抗性程序。 验证本提案中提出的假设将在以下领域产生重大影响： 衰老生物学和肿瘤免疫学，以及衰老诱导疗法作为临床治疗的用途。 癌症治疗学

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.