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

总结： 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应答 （NSCLC）。然而，大多数患者并没有从治疗中获益，那些最初有反应的患者最终 发展出获得性抵抗力。这些临床情况的治疗选择有限。以基本 为了降低NSCLC死亡率，必须：i）鉴定新的生物标志物，用于最佳选择患者， ii）发现PD-1/PD-L1轴以外的免疫治疗靶点，可用于治疗患有PD-1/PD-L1轴的患者。 iii）揭示免疫在肿瘤进展过程中的作用，以设计早期治疗方案， 干预措施。我们小组最近的研究确定了基线T细胞功能障碍和LAG-3上调， NSCLC中PD-1阻断耐药的关键决定因素。我们还发现，LAG-3信号转导诱导 T细胞凋亡，并鉴定FGL 1为癌症中的主要抑制性LAG-3配体。我们假设 LAG-3/FGL 1通路的参与介导了显性免疫逃避和T细胞功能障碍/死亡， 对PD-1疗法不敏感的NSCLC亚组。在这个项目中，通过3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志物方面的专业知识：i）确定 ii）分析LAG-3/FGL 1的机制和作用 iii）检查LAG-3/FGL 1在人肺恶性肿瘤中作为免疫调节靶标的作用 通路和免疫环境在肺癌发生和早期肺癌进展中的作用。这项工作的结果 将加速将研究概念转化为临床，以建立新的生物标志物，支持 解释临床试验并为早期和晚期肺癌设计最佳治疗方式。

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.