Strategies to predict and overcome resistance to cancer immunotherapy

PD-1阻断等免疫疗法彻底改变了癌症护理。然而 大多数患者没有从T细胞阻断中获得持续（持久）的益处， 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 缺乏免疫治疗抗性。这两个差距反映了我们的不完整 了解T细胞是如何实现持久免疫的。祖T 细胞通常平衡相互对立的分化和自我调节的需求， 通过向子细胞传递不等的合成代谢激活信号来更新。在 然而，在癌症的情况下，持续的T细胞活化会使正常的T细胞活化发生扭曲。 平衡分化和更新的再生平衡 分化细胞的功能障碍沿着自我更新T细胞的进行性丧失。它 先前假定PD-1阻断通过将效力恢复到最大程度而起作用。 功能失调的T细胞相反，新的共识表明，PD-1 阻断只能通过诱导更大的自我分裂和分化来发挥作用， 更新已经处于危险中的T细胞。这种临床前和转化应用 整理了我们关于T细胞信号传导和细胞生物学的基本发现， 再生，以解决癌症护理的主要临床障碍。实现以下目标： 该建议将能够确定1）是否具有抗癌免疫力， 免疫疗法影响CD 8 + T细胞的自我更新; 2）免疫疗法是否可以 通过增强CD 8 + T细胞自我更新得到改善;以及3）患者的反应是否 和对免疫检查点阻断的抗性可以从 自我更新的T细胞该提案将解决两个关键的未满足的患者需求： 用于对免疫疗法的应答和抗性的非侵入性预测生物标志物 和一种新的耐药导向治疗策略， 免疫疗法使大多数人受益，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.