Excessive lipid metabolism in T cell senescence and immunosuppression

项目摘要/摘要 目前的免疫疗法，包括免疫检查点阻断疗法和过继T细胞疗法，已经 在某些类型的癌症患者中取得了令人振奋的结果。然而，到目前为止，这些免疫疗法已经取得了 不足以重复消除肿瘤。很明显，肿瘤反应性T细胞受到抑制， 抑制性肿瘤微环境功能失调是肿瘤成功的主要障碍 免疫疗法。因此，剖析导致T细胞功能障碍状态的不同机制 抑制性肿瘤微环境为肿瘤免疫治疗提供了新的途径。 我们发现，诱导T细胞衰老是一种重要的T细胞功能失调状态，是一种新的 人类自然产生的和肿瘤来源的调节性T(Treg)细胞共同利用的抑制机制 在肿瘤微环境中。事实上，也发现了衰老的CD8+T细胞的显著积累 在不同类型癌症患者的肿瘤浸润性T细胞(TIL)中。重要的是，我们发现这些 衰老的T细胞在功能上受到抑制，在分子上有别于无能和衰竭的T细胞和 它们是肿瘤微环境中免疫抑制的关键介体和放大器。 因此，对这一新的抑制机制和分子过程有了更好的理解。 由Treg细胞抑制的反应性T细胞对于开发有效的治疗策略至关重要 人类癌症。细胞能量代谢决定T细胞的存活、增殖及其特定功能。 不同的T细胞亚群具有不同的代谢谱。我们最近发现，Treg诱导的 衰老的T细胞表现出活跃的脂代谢，导致脂代谢酶和 分泌类脂种类和脂滴(LDS)积累。这项提议的核心假设是 认为：1)过多的脂代谢是影响机体衰老发育和免疫抑制的重要因素。 由Treg细胞介导的T细胞；2)衰老和功能障碍的肿瘤特异性T细胞可以通过 脂质重编程以增强抗肿瘤免疫力。具体目标1试图确定过度的 脂代谢参与Treg诱导的T细胞衰老发育和免疫抑制 细胞。具体目标2将探索新的概念并开发有效的策略来克服衰老 通过脂代谢重编程结合选择性检查点来耗尽肿瘤特异性T细胞 阻断抗PDL1抗体增强过继T细胞转移治疗肿瘤的抗肿瘤效应 模特们。这些研究的积极结果应该会导致重新编程脂代谢的新策略 以及肿瘤特异性T细胞在癌症治疗中的效应功能。

PROJECT SUMMARY/ABSTRACT Current immunotherapies, including immune checkpoint blockage therapy and adoptive T cell therapy, have resulted in promising results in certain types of cancer patients. However, these immunotherapies have so far been insufficient to reproducibly eliminate tumors. It is clear that tumor-reactive T cells are suppressed and dysfunctional in the suppressive tumor microenvironment that is a major obstacle for successful tumor immunotherapy. Thus, dissecting the distinct mechanisms responsible for T cell dysfunctional states within the suppressive tumor microenvironment should provide novel avenues for tumor immunotherapy. We discovered that induction of T cell senescence is an important T cell dysfunctional state and a novel suppressive mechanism utilized by both human naturally occurring and tumor-derived regulatory T (Treg) cells in the tumor microenvironment. In fact, significant accumulation of senescent CD8+ T cells has also been found in the tumor-infiltrating T cells (TILs) from various types of cancer patients. Importantly, we found that these senescent T cells are functionally suppressive and molecularly distinct from anergic and exhausted T cellsand that they are a critical mediator and amplifier for immune suppression within the tumor microenvironments. Therefore, a better understanding of this novel suppressive mechanism and the molecular processes in responder T cells suppressed by Treg cells is essential for the development of effective strategies to treat human cancers. Cellular energy metabolism directs T cell survival, proliferation and their specific functions. Different T cell subsets have different metabolic profiles. We have more recently identified that Treg-induced senescent T cells exhibit active lipid metabolism, resulting in upregulation of lipid metabolic enzymes and secretory lipid species, and accumulation of lipid droplets (LDs). The central hypotheses of this proposal are that: 1) Excessive lipid metabolism is critical for senescence development and immunosuppression of effector T cells mediated by Treg cells; 2) Senescent and dysfunctional tumor-specific T cells can be rejuvenated via lipid reprogramming for enhanced anti-tumor immunity. Specific Aim 1 seeks to identify whether the excessive lipid metabolism is involved in senescence development and immunosuppression of T cells induced by Treg cells. Specific Aim 2 will explore the novel concept and develop effective strategies to overcome senescent and exhausted tumor-specific T cells via lipid metabolism reprogramming combined with selective checkpoint blockage therapy of anti-PDL1 for enhanced anti-tumor efficiency in the adoptive T cell transfer therapy tumor models. The positive outcome of these studies should lead to novel strategies to reprogram lipid metabolism and effector functions of tumor-specific T cells for cancer treatments.