Mechanisms of resistance to immune therapy in NSCLC

摘要 尽管已被批准作为非小细胞肺癌（NSCLC）的一线和二线治疗，但抗PD-1抗体仍是治疗NSCLC的有效药物。 1抗体在相当大比例的肺癌患者中仍然失败。失败背后的机制 抗PD-1治疗在大多数NSCLC患者中的作用尚未完全了解。我们发现，在 抗PD-1抗性LSL-KrasG 12 D鼠肺腺癌小鼠模型，治疗诱导T细胞 在一些实施方案中，所述活化谱有利于Th 17/γδT17复苏超过CD 8 + T细胞活化。相反，当 在与抗IL-17中和抗体联合施用的情况下，抗PD-1治疗导致显著的免疫应答。 增强CD 8 + T细胞的细胞毒性，几乎完全根除已建立的疾病。这些发现 为我们的中心假设提供了前提，即在NSCLC中，抗PD-1的失败至少部分是由于 PD-1+ 17型T细胞（Th 17/γδT17）的复苏，其积极破坏抗PD-1介导的恢复 CD 8 + T细胞的细胞毒性功能。基于额外的小鼠数据，我们也在推进扩展的 假设肿瘤性肺中预先存在的T17活性的严重程度是由肿瘤性肺组织中的T17活性决定的， 肺微生物群特征可以最终预测对抗PD-1治疗的反应性。的 本提案的目的是在启动R 01之前证明这些发现与人类的相关性 应用程序.具体而言，在目标1中，我们将确定肺固有T17/CTL比率是否预测抗PD-1抗体。 NSCLC患者的1应答性与新抗原负荷无关。在目标2中，我们将确定 特定的人肺微生物群，单独或以限定的组合，驱动内在T17的个体发生 免疫力和最终对ICI疗法的抗性。拟议的研究在概念上具有影响力，因为它解决了 一个重要的临床难题;在机制上是新颖的;并且具有翻译相关性，因为它引入 治疗/预后方法，可以迅速转移到临床。

ABSTRACT Despite having been approved as first and second line therapy for non-small cell lung cancer (NSCLC), anti-PD- 1 antibodies still fail in a substantial proportion of lung cancer patients. The mechanism that underlies the failure of anti-PD-1 therapy in the majority of NSCLC patients is not yet fully understood. We have discovered that, in the anti-PD-1-resistant LSL-KrasG12D murine lung adenocarcinoma mouse model, treatment induces a T-cell activation profile that favors Th17/γδT17 reinvigoration over CD8+ T cell activation. In contrast, when administered in conjunction with an anti-IL-17 neutralizing antibody, anti-PD-1 treatment results in a dramatic enhancement of CD8+ T-cell cytotoxicity with near-complete eradication of established disease. These findings provide the premise for our central hypothesis that in NSCLC, the failure of anti-PD-1 is, at least in part, due to reinvigoration of PD-1+ type 17 T cells (Th17/γδT17), which actively undermine anti-PD-1-mediated restoration of cytotoxic function in CD8+ T-cells. Based on additional murine data, we are also advancing the extended hypothesis that the severity of pre-existing T17 activity in the neoplastic lung is determined by commensal bacteria and that the lung microbiota signature can ultimately predict responsiveness to anti-PD-1 therapy. The goal of this proposal is to demonstrate the relevance of these findings to human prior to initiating an R01 application. Specifically, in Aim 1, we will establish whether intrinsic lung T17/CTL ratio is predictive of anti-PD- 1 responsiveness in NSCLC patients independent of neoantigen burden. In Aim 2 we will determine whether specific human lung microbiota, individually or in defined combinations, drive the ontogeny of intrinsic T17 immunity and ultimately resistance to ICI therapy. The proposed study is conceptually impactful as it addresses an important clinical conundrum; is mechanistically novel; and has translational relevance since it introduces therapeutic/prognostic approaches that can rapidly move to the clinic.