Strategies to predict and overcome resistance to cancer immunotherapy

PD-1阻断等免疫疗法使癌症治疗发生了革命性的变化。还没有 大多数患者没有从T细胞阻断中获得持续(持久)的好处 抑制性受体。不幸的是，目前的生物标志物不能充分预测患者 对免疫疗法的反应或抵抗；以及克服的成功策略 免疫治疗一直缺乏抵抗力。这两个差距都反映了我们的不完整 了解T细胞如何实现持久免疫。祖细胞T 细胞通常平衡分化和自我分化的相互对立的需求 通过向子代细胞传递不相等的合成代谢激活信号进行更新。在 然而，癌症的背景下，持续的T细胞激活扭曲了正常 均衡分化与渐进式更新的再生均衡 分化细胞功能障碍与自我更新T细胞进行性丧失。它 之前被认为PD-1的阻断是通过最大限度地恢复效力来起作用的 功能失调的T细胞。相反，新出现的共识表明，PD-1 封锁只有通过诱导更大的自我分裂和分化才能发挥作用 更新已经处于危险之中的T细胞。这种临床前和转化性应用 总结了我们关于T细胞信号和细胞生物学的基本发现 再生，以解决癌症护理中的一个主要临床障碍。实现以下目标 这项建议将使1)确定抗癌免疫力和 免疫治疗对CD8 T细胞自我更新的影响；2)免疫治疗能否 通过增强CD8 T细胞自我更新来改善；以及3)患者的反应 而对免疫检查点封锁的抵抗力可以从丰富的 自我更新的T细胞。这项提议将解决两个关键的未得到满足的患者需求：a 免疫治疗应答和抵抗的非侵入性预测生物标志物 跨癌症类型；以及一种新的耐药定向治疗策略 免疫治疗要造福大多数患者，而不是少数患者。

Immunotherapies such as PD-1 blockade have revolutionized cancer care. Yet most patients do not experience sustained (durable) benefit from blockade of T cell inhibitory receptors. Unfortunately, current biomarkers do not adequately predict patient response or resistance to immunotherapy; and successful strategies to overcome immunotherapy resistance have been lacking. Both gaps reflect our incomplete understanding of how durable immunity carried out by T cells is achieved. Progenitor T cells normally balance the mutually opposing demands of differentiation and self- renewal by transmitting unequal anabolic activating signals to daughter cells. In the setting of cancer, however, sustained T cell activation skews the normal regenerative equilibrium of balanced differentiation and renewal towards progressive dysfunction of differentiated cells along with progressive loss of self-renewing T cells. It was previously presumed that PD-1 blockade acted by restoring potency to the most dysfunctional T cells. Instead, emerging consensus has demonstrated that PD-1 blockade can only function by inducing greater division and differentiation of self- renewing T cells, which are already in peril. This preclinical and translational application marshals our basic discoveries concerning the signaling and cell biology of T cell regeneration to tackle a major clinical roadblock in cancer care. Performing the aims of this proposal will enable determination of 1) whether anti-cancer immunity and immunotherapy impact the self-renewal of CD8+ T cells; 2) whether immunotherapy can be improved by augmenting CD8+ T cell self-renewal; and 3) whether patient response and resistance to immune checkpoint blockade can be predicted from the abundance of self-renewing T cells. This proposal would address two critical unmet patient needs: a non-invasive predictive biomarker for response and resistance to immunotherapy across cancer types; and a novel strategy for resistance-directed treatment enabling immunotherapy to benefit the majority, rather than the minority of patients.