Investigation of Immune Modulation and Its Correlation to Response in Early Stage Lung Cancer Patients Receiving Neo-adjuvant Immunotherapy

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Lung cancer is the leading cause of cancer-related death worldwide. Non-Small Cell Lung Cancer (NSCLC) is its major subtype. Most patients are diagnosed at an advanced stage of disease and have a poor prognosis. Recent breakthroughs in cancer immunology suggest that immune-checkpoint blockade (ICB) can activate the immune response. ICB with anti-PD-1 or anti-PD-L1 shows promising efficacy and is associated with increased overall survival in NSCLC. However, only 15-20% of patients show a long-term benefit. Besides influencing the anti-tumor response, ICB could also induces inflammatory immune-related adverse events (irAEs). Tumor-draining lymph nodes (TDL) play a crucial role in cancer development, progression and immunity. The lung lymphatic drainage spans from intrapulmonary lymph nodes (LN) to hilar and mediastinal LN. How ICB impacts immune cell activation, as well as immunophenotype shifting in TDL, blood, and tumor microenvironment is not fully understood. The James Thoracic Center is currently leading a multicenter, investigator-initiated, Phase II trial to investigate the efficacy and safety of a neoadjuvant immunotherapy (NIT) with anti-PD-L1 agent atezolizumab in patients with resectable and untreated NSCLC. As part of this clinical trial, LN will be sampled prior to NIT and at the time of surgery. Blood and tumor samples will be taken as well.The central hypothesis is that ICB with anti-PD-L1 will promote tumor-specific T-cell activation and clonal expansion, as well as immunophenotype shifting in TDL, blood, and tumor microenvironment, leading to an anti-tumor immune response in NSCLC. To test this hypothesis, we will conduct research with three specific aims: Aim1 Quantitatively analyze lymphocyte populations in tumor-infiltrated and non-tumor infiltrated LN of NSCLC patients using pre- and post-treatment mediastinal and hilar LN samples (surgical and EBUS-TBNA) to evaluate for shifts in the immune microenvironment. Aim2 Quantitatively analyze circulating cytokines and circulating cell immunophenotypes in pre- and post-treatment blood samples, track T-cell activation/clonal expansion, and correlate with nodal immunophenotype changes. Aim3 Correlate data from Aims1 and 2 with quantitative analysis of tumor-infiltrating immune cell populations and comprehensive tumor genomics acquired by collaborating institutions, and with response and irAEs in patients. This project will investigate immune modulation and its correlation to response in early stage NSCLC patients receiving neo-adjuvant anti-PD-L1 therapy. This will help to better understand the immune response mechanism in lung cancer and to meet the crucial need for developing immune-related biomarkers and optimizing immunotherapy in lung cancer. This research will also shed light on lung immune modulation mechanism and pathophysiology in general, laying a foundation for future immunity related investigation and translation in both malignant and benign lung diseases.