Mechanisms of PD-1 and Tim-3 crosstalk in tumor-infiltrating lymphocytes

 描述（由申请人提供）：“检查点”受体的新兴领域揭示了适应性免疫系统缩小或消除肿瘤的潜在且强大的能力。检查点抑制剂（如抗PD-1）的单一药物应答率仍然相对较低，初步结果表明组合方法显着更有效。最近的研究表明，PD-1和新出现的检查点分子Tim-3的共表达在肿瘤浸润淋巴细胞（TIL）中很常见，临床前数据表明PD-1和Tim-3的联合靶向对肿瘤消退产生协同作用。然而，目前尚不清楚靶向这些蛋白质的抗体如何在单一或双重治疗中调节下游信号传导事件。耐药（或治疗逃逸）也可能是由于阻断单一受体后替代检查点受体的“补偿性”上调，部分由细胞内信号“串扰”介导。“这些蛋白质之间的分子或功能合作尚未在人类癌症患者新鲜分离的TIL中进行研究。有趣的是，已知PI 3 K/Akt/mTOR信号通路分别被PD-1或Tim-3抑制或激活，这表明该信号通路是调节T细胞耗竭的重要节点。基于新出现的数据，我们假设PD-1和Tim-3协同控制肿瘤浸润的耗尽/效应CD 8 + T细胞的功能，并且PD-1和Tim-3信号传导串扰的调节调节癌症中的T细胞受体（TCR）活化。我们建议确定头颈癌（HNC）患者肿瘤浸润活化与耗竭CD 8 + CTL中Tim-3/PD-1信号传导和功能串扰的途径。然后，我们将确定Tim-3在HNC小鼠模型中改变PD-1对活化的效应物相对于耗尽的CTL的作用的程度。最后，我们将确定对PD-1或Tim-3阻断的代偿性ICR表达和功能的途径。

 DESCRIPTION (provided by applicant): The emerging field of "checkpoint" receptors has revealed a latent, and powerful, ability of the adaptive immune system to shrink or eliminate tumors. Single agent response rates for checkpoint inhibitors, such as anti-PD-1 are still relatively low and preliminary results suggest that combinatorial approaches are significantly more effective. Recent studies have demonstrated that co-expression of PD-1 and the emerging checkpoint molecule Tim-3 is frequent in tumor infiltrating lymphocytes (TIL) and pre-clinical data suggest that combined targeting of PD-1 and Tim-3 produces synergistic effects on tumor regression. However, it is not clear how antibodies targeting these proteins, either in mono- or duo-therapy, modulate downstream signaling events. Resistance (or therapeutic escape) could also occur due to "compensatory" upregulation of an alternative checkpoint receptor after blockade of a single receptor, mediated in part by intracellular signaling "cross talk." Molecular or functional cooperation between these proteins has not been examined in the context of freshly isolated TIL from human cancer patients. Intriguingly, the PI3K/Akt/mTOR signaling pathway is known to be inhibited or activated by PD-1 or Tim-3, respectively, suggesting that this signaling pathway is an important node for the regulation of T cell exhaustion. Based on emerging data, we hypothesize that PD-1 and Tim-3 cooperate to control the function of tumor-infiltrating exhausted/effector CD8+ T cells, and that modulation of PD-1 and Tim-3 signaling cross-talk modulates T cell receptor (TCR) activation in cancer. We propose to define pathways of Tim-3/PD-1 signaling and functional crosstalk in tumor-infiltrating activated vs exhausted CD8+ CTL from head and neck cancer (HNC) patients. We will then determine the extent to which Tim-3 modifies the effects of PD-1 on activated effector vs. exhausted CTL in a mouse model of HNC. Lastly, we will define pathways of compensatory ICR expression and function in response to PD-1 or Tim-3 blockade.