Targeting T Cell Senescence and Dysfunction for Anti-tumor Immunity

项目摘要/摘要 目前的免疫治疗策略，包括针对CTLA-4和/或的免疫检查点阻断治疗 PD1/PD-L1，已经在某些类型的癌症患者中产生了令人振奋的结果。然而，总体上取得了成功 这些战略的比率仍然从15%到35%不等，这表明还有其他机制和/或 涉及对恶性肿瘤介导的治疗无反应的检查点信号。因此， 针对更特定的检查点分子或干扰耐受通路的替代新策略 都是迫切需要的。现已认识到肿瘤反应性T细胞的抑制和功能障碍 调节性T细胞(Treg)在肿瘤抑制微环境中的诱导是治疗肿瘤的主要障碍 成功的抗肿瘤免疫治疗。我们最近发现了一种新的抑制机制， 人类Treg细胞诱导效应T细胞衰老，然后显示出强大的抑制活性和 放大免疫抑制。因此，对细胞和分子过程的更好理解 控制Treg诱导的效应性T细胞衰老对于制定有效的治疗策略至关重要 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- Treg诱导衰老T细胞脂代谢的调节。此外，ATM相关的DNA损伤 应答和MAPK信号通路选择性地参与了人Treg细胞介导的T细胞衰老。 此外，我们还发现，人类Toll样受体8(TLR8)信号可逆转这种抑制作用 功能，并防止自然产生的Treg和肿瘤介导的T细胞衰老 衍生的Treg细胞。这一提议的中心假设是：1)人类Treg细胞可以选择性地 调节分子程序，重写经处理的幼稚/效应T细胞中的T细胞脂代谢，导致 它们分化为衰老的T细胞；2)衰老和功能失调的肿瘤特异性T细胞可以 通过检查点阻断应答T细胞中的ATM和MAPK信号而恢复活力，与TLR8结合 Treg细胞中的信号激活，导致增强的抗肿瘤免疫反应。具体目标1旨在 确定导致应答者衰老和功能障碍的分子机制(S) 与Treg细胞相互作用后的T细胞。我们将剖析Treg细胞如何分子重写效应器T细胞的命运 和脂类代谢。目标2将测试TLR8介导的重新编程的新概念和策略 Treg细胞的葡萄糖代谢与选择性MAPK和/或ATM的检查点阻断- 应答T细胞中相关DNA损伤信号可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。这些措施的一个积极结果 研究应该导致新的策略来重新编程Treg代谢并控制TREG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.