Project 2: Targeting Immune Vulnerabilities in Lung Cancer

项目2概要/摘要 PD-1/PD-L1检查点阻断（PCB）单独或与化疗联合免疫治疗现在代表了 携带野生型EGFR和ALK的NSCLC患者的标准一线治疗。这是一个重大的进步， 但大多数NSCLC患者对PCB没有客观反应。的分子决定因素 PCB耐药性尚不完全清楚，尽管低肿瘤突变负荷和PD-L1水平预测 一些案件。最近，我们报道了LKB 1缺陷（LD）肿瘤是由LKB 1基因突变或缺失引起的。 STK 11/LKB 1基因与惰性或“冷”免疫表型相关，并代表最大的 基因组学定义的亚组具有对PCB的主要抗性，占PCB抗性的30%以上 在肺腺癌中。LKB 1蛋白是代谢、能量平衡和代谢的主要调节剂。 核苷酸储存。我们小组和其他人最近的出版物表明，LD肿瘤具有明显的 代谢表型，包括增强的乳酸产生，靶向细胞内核苷酸的脆弱性， 途径，并增加复制应力（RS）。这些特征可能有助于“冷”免疫表型。 项目2（P2）的主要目标是研究靶向LD NSCLC的新治疗方法， 增强抗肿瘤免疫力，重点针对乳酸途径和RS。这一重点整合了 项目2的免疫治疗重点与其他SPORE项目的研究相结合，并提供多种人类免疫治疗。 SPORE项目的端点。我们假设：1）乳酸产生或分泌增加 导致LD NSCLC中的“冷”免疫表型; 2）LD NSCLC将优先易受 靶向RS;和3）靶向RS和/或乳酸途径可以增强抗肿瘤免疫和对 PCB。为了验证这些假设，在SA 1中，我们将全面描述LD的免疫表型 使用两组切除肿瘤的NSCLC：MD安德森ICON队列和UTSW的验证队列 它们在P1中经历了代谢标记。我们还将使用单克隆抗体更详细地检查免疫细胞。 细胞RNA测序。在SA 2中，我们将测试是否使用MCT 4抑制剂靶向乳酸途径， LDHA可以逆转LD相关的免疫抑制并增强PCB疗效。在SA 3中，我们将以RS为目标 单独或联合使用ATM、ATR和核苷类似物6-硫代-dG的抑制剂与P4， 结合PCB。意义：LD NSCLC肿瘤具有“冷”免疫表型， 对多氯联苯或多氯联苯/化疗的抗性。该患者人群大于EGFR突变型NSCLC， 可能是转移性胰腺癌。P2旨在利用我们独特的临床和临床前 为LD NSCLC患者开发更有效的治疗方法，然后可以将其转化为 被我们的团队和其他人带到了诊所P2还提供了一个机会， 基因组指导的，针对PCB耐药肿瘤的定制免疫疗法。

Project 2 Summary/Abstract Immunotherapy with PD-1/PD-L1 checkpoint blockade (PCB) given alone or with chemotherapy now represents the standard first-line treatment for NSCLC patients with wild-type (wt) EGFR and ALK. This is a major advance, but the majority of NSCLC patients do not have an objective response to PCB. The molecular determinants of PCB resistance are incompletely understood, although low tumor mutation burden and PD-L1 levels predict some cases. Recently, we reported that LKB1 deficient (LD) tumors resulting from mutations or deletions in the STK11/LKB1 gene are associated with an inert or “cold” immune phenotype and represent the largest genomically-define subgroup with primary resistance to PCB, accounting for more than 30% of PCB resistance in lung adenocarcinoma. The LKB1 protein is a master regulator of metabolism, energetic balance, and nucleotide stores. Recent publications from our group and others indicate that LD tumors have a distinct metabolic phenotype that includes enhanced lactate production, vulnerability to targeting intracellular nucleotide pathways, and increased replicative stress (RS). These features may contribute to the “cold” immune phenotype. The primary goals of Project 2 (P2) are to investigate new therapeutic approaches for targeting LD NSCLC and enhancing antitumor immunity, with a focus on targeting the lactate pathway and RS. This focus integrates the immunotherapy focus of Project 2 with studies in the other SPORE Projects and provides multiple Human Endpoints for the SPORE Projects. We hypothesize that: 1) Enhanced lactate production or secretion contributes to the “cold” immune phenotype in LD NSCLC; 2) LD NSCLC will be preferentially vulnerable to targeting RS; and 3) targeting RS and/or lactate pathways may enhance antitumor immunity and response to PCB. To test these hypotheses, in SA1 we will comprehensively characterize the immune phenotypes of LD NSCLC using two sets of resected tumors: the MD Anderson ICON cohort and a validation cohort from UTSW which have undergone metabolic labeling in P1. We will also examine immune cells in greater detail using single cell RNA sequencing. In SA2 we will test whether targeting the lactate pathway using inhibitors of MCT4 and LDHA can reverse LD-associated immunosuppression and enhance PCB efficacy. In SA3, we will target RS using inhibitors of ATM, ATR, and the nucleoside analog 6-thio-dG in collaboration with P4, alone or in combination with PCB. Significance: LD NSCLC tumors have a “cold” immune phenotype and frequent primary resistance to PCB or PCB/chemotherapy. This patient population is larger than EGFR-mutant NSCLC and comparably sized to metastatic pancreatic cancer. P2 aims to leverage our unique set of clinical and preclinical resources to develop more effective therapeutic approaches for LD NSCLC patients, which can then translated by our group and others into the clinic. P2 also provides the opportunity to spearhead a new paradigm of genomically-guided, tailored immunotherapy for PCB-resistant tumors.