Quantitative and Spatially-Resolved Analysis of the Tumor Immune Contexture for Optimal Diagnosis and Treatment of Lung Cancer

摘要： PD-1轴阻滞剂在约20%的非小细胞肺癌患者中诱导持久的临床反应 (NSCLC)。然而，大多数患者并没有从治疗中受益，那些最初有反应的患者最终也没有受益。 产生后天抵抗力。对于这些临床情况，治疗选择有限。到实质上 要降低非小细胞肺癌死亡率，当务之急是：i)确定新的生物标志物，以便最佳地选择患者 治疗；ii)发现PD-1/PD-L1轴以外的免疫治疗靶点，可用于治疗 难治性肿瘤；以及iii)揭示免疫在肿瘤进展中的作用，以设计早期治疗 干预措施。我们小组最近的研究发现基线T细胞功能障碍和LAG-3上调是 非小细胞肺癌抵抗PD-1阻断的关键决定因素。我们还发现，LAG-3信号诱导 T细胞凋亡，并确定FGL1是癌症中主要的抑制性LAG-3配体。我们假设 LAG-3/FGL1通路参与介导A细胞的显性免疫逃避和T细胞功能障碍/死亡 对PD-1治疗不敏感的NSCLC亚群。在这个项目中，通过三个互补的目标，我们将 利用我们在癌症免疫生物学和生物标记物方面的专业知识：i)确定 检测非小细胞肺癌患者的TIL功能；II)分析LAG-3/FGL1的机制和作用 作为免疫调节靶点的相互作用在人类肺部恶性肿瘤中的作用；以及iii)检测LAG-3/FGL1的作用 癌变和早期肺癌进展中的途径和免疫环境。这项工作的结果 将加快将研究概念转化为临床，以建立新的生物标志物，支持 解释早期和晚期肺癌的临床试验和设计最佳治疗方案。

Summary: PD-1 axis blockers induce durable clinical responses in ~20% of patients with non-small cell lung cancer (NSCLC). However, most patients do not benefit from treatment and those who initially respond ultimately develop acquired resistance. There are limited treatment options for these clinical scenarios. To substantially reduce NSCLC mortality, it is imperative to: i) Identify novel biomarkers for optimal selection of patients for treatment; ii) Uncover immunotherapy targets beyond the PD-1/PD-L1 axis that may serve to treat patients with refractory tumors; and iii) Reveal the role of immunity during tumor progression to design early therapeutic interventions. Recent studies from our group identified baseline T-cell dysfunction and LAG-3 upregulation as key determinants for resistance to PD-1 blockade in NSCLC. We have also found that LAG-3 signaling induces T-cell apoptosis and identified FGL1 as major inhibitory LAG-3 ligand in cancer. We hypothesize that engagement of the LAG-3/FGL1 pathway mediates dominant immune evasion and T-cell dysfunction/death in a subset of NSCLCs insensitive to PD-1 therapies. In this project and through 3 complementary aims, we will leverage our expertise in cancer immunobiology and biomarkers to: i) Determine the biomarker value of measuring functional TIL profiles in human NSCLC; ii) Analyze the mechanisms and role of LAG-3/FGL1 interaction as immunomodulatory target in human lung malignancies; and iii) Examine the role LAG-3/FGL1 pathway and immune contexture in carcinogenesis and early lung cancer progression. The results from this work will accelerate translation of research concepts into the clinic for establishment of novel biomarkers, support interpretation of clinical trials and design optimal treatment modalities for early-stage and advanced lung cancer.