Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity

项目总结/摘要 目前的免疫治疗策略，包括靶向CTLA-4和/或CTLA-4受体的免疫检查点阻断治疗， PD 1/PD-L1在某些类型的癌症患者中产生了有希望的结果。然而，总体成功 这些策略的使用率仍然在15%到35%之间，这表明还有其他机制和/或 检查点信号转导参与对恶性肿瘤介导的治疗无反应。因此，在本发明中， 靶向更特异性检查点分子或中断致耐受性途径的替代新策略 是迫切需要的。现在已经充分认识到，肿瘤反应性T细胞的抑制和功能障碍 在肿瘤抑制微环境中由调节性T细胞（Treg）诱导的免疫应答是肿瘤抑制的主要障碍。 成功的抗肿瘤免疫疗法。我们最近发现了一种新的抑制机制， 人Treg细胞诱导效应T细胞中的衰老，所述效应T细胞随后表现出有效的抑制活性， 增强免疫抑制因此，更好地理解细胞和分子过程， 控制效应T细胞中Treg诱导的衰老对于开发有效的策略至关重要， 治疗人类癌症我们发现能量传感器AMPK和dys的激活显著增加， 调节Treg诱导的衰老T细胞中的脂质代谢。此外，ATM相关的DNA损伤 应答和MAPK信号传导选择性地参与人Treg细胞介导的T细胞衰老。 此外，我们还发现人Toll样受体8（TLR 8）信号转导逆转了抑制性Toll样受体表达。 功能，并防止由天然存在的Treg和肿瘤介导的T细胞衰老的诱导， Treg细胞。该提议的中心假设是：1）人Treg细胞可以选择性地 调节分子程序，在治疗的幼稚/效应T细胞中重写T细胞脂质代谢，导致 它们分化成衰老T细胞; 2）衰老和功能障碍的肿瘤特异性T细胞可以是 通过ATM和应答T细胞中MAPK信号传导的检查点阻断，结合TLR 8， 在Treg细胞中的信号传导激活，导致增强的抗肿瘤免疫应答。具体目标1： 确定诱导应答者衰老和功能障碍的分子机制 与Treg细胞相互作用后的T细胞。我们将剖析Treg细胞如何在分子上改写效应T细胞的命运 和脂质代谢。目的2将测试TLR 8介导的细胞重编程的新概念和策略， 在Treg细胞中的葡萄糖代谢与选择性MAPK和/或ATM的检查点阻断相结合。 应答T细胞中相关的DNA损伤信号传导可以协同增强抗肿瘤免疫 通过逆转肿瘤特异性T细胞的衰老和功能障碍。这些积极成果 研究应该导致新的策略来重新编程Treg代谢和控制Treg代谢的命运和功能。 用于治疗人类癌症的肿瘤特异性T细胞。

PROJECT SUMMARY/ABSTRACT Current immunotherapy strategies, including immune checkpoint blockade therapy targeting CTLA-4 and/or PD1/PD-L1, have yielded promising results in certain types of cancer patients. However, the overall success rates of these strategies still vary from 15% to 35%, which suggests that there are other mechanisms and/or checkpoint signaling involved that are unresponsive to therapy mediated by malignant tumors. Thus, alternative novel strategies targeting more specific checkpoint molecules or interrupting tolerogenic pathways are urgently needed. It is now well recognized that the suppression and dysfunction of tumor-reactive T cells induced by regulatory T cells (Treg) in the tumor suppressive microenvironment present a major barrier for successful anti-tumor immunotherapy. We recently discovered a novel suppressive mechanism whereby human Treg cells induce senescence in effector T cells that then exhibit potent suppressive activity and amplify immune suppression. Therefore, a better understanding of the cellular and molecular processes that control Treg-induced senescence in effector T cells is essential for the development of effective strategies to treat human cancer. We identified significantly increased activation of the energy sensor AMPK and dys- regulation of lipid metabolism in Treg-induced senescent T cells. Furthermore, ATM-associated DNA damage response and MAPK signaling were selectively involved in T cell senescence mediated by human Treg cells. In addition, we have discovered that human Toll-like receptor 8 (TLR8) signaling reverses the suppressive function and prevents the induction of T cell senescence mediated by both naturally occurring Treg and tumor- derived Treg cells. The central hypotheses of this proposal are that: 1) Human Treg cells can selectively modulate molecular programs that rewrite T cell lipid metabolism in treated naïve/effector T cells, resulting in their differentiation into senescent T cells; 2) Senescent and dysfunctional tumor-specific T cells can be rejuvenated via checkpoint blockages of ATM and MAPK signaling in responder T cells, combined with TLR8 signaling activation in Treg cells, resulting in enhanced anti-tumor immune responses. Specific Aim 1 seeks to identify the molecular mechanism(s) responsible for the induction of senescence and dysfunction in responder T cells after interaction with Treg cells. We will dissect how Treg cells molecularly rewrite effector T cell fate and lipid metabolism. Aim 2 will test the novel concept and strategy that TLR8-mediated reprogramming of glucose metabolism in Treg cells combined with checkpoint blockage of selective MAPK and/or ATM- associated DNA damage signaling in responder T cells can synergistically enhance anti-tumor immunity through reversing the senescence and dysfunction of tumor-specific T cells. A positive outcome of these studies should lead to novel strategies to reprogram Treg metabolism and control the fate and function of tumor-specific T cells for the treatment of human cancers.