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和强大的能力。对于检查点抑制剂，如抗PD-1，单一药物的应答率仍然相对较低，初步结果表明，联合治疗明显更有效。最近的研究表明，PD-1和新出现的检查点分子TIM-3在肿瘤浸润性淋巴细胞(TIL)中经常共同表达，临床前数据表明，PD-1和TIM-3的联合靶向在肿瘤消退中产生了协同作用。然而，目前还不清楚针对这些蛋白的抗体，无论是在单一疗法还是双重疗法中，如何调节下游信号事件。抗性(或治疗逃逸)也可能是由于阻断单一受体后，另一种检查点受体“代偿性”上调所致，这部分是由细胞内信号“串扰”介导的。这些蛋白质之间的分子或功能合作还没有在人类癌症患者新鲜分离的TIL的背景下进行检查。有趣的是，PI3K/Akt/mTOR信号通路分别被PD-1或Tim-3抑制或激活，提示该信号通路是调节T细胞耗竭的重要节点。根据新的数据，我们假设PD-1和TIM-3协同控制肿瘤浸润性耗尽/效应CD8+T细胞的功能，并且PD-1和TIM-3信号串扰的调节调节肿瘤中T细胞受体(TCR)的激活。我们建议在头颈癌(HNC)患者的肿瘤浸润性激活的CD8+CTL和耗竭的CD8+CTL中确定TIM-3/PD-1信号和功能串扰的通路。然后，我们将确定在HNC小鼠模型中，TIM-3在多大程度上修改PD-1对激活的效应器和疲惫的CTL的影响。最后，我们将确定响应PD-1或TIM-3阻断的ICR代偿性表达和功能的途径。

 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.