Immune reactivity across the spectrum of disease in lung adenocarcinoma

During initiation and progression, tobacco-induced lung cancer may acquire hundreds of different somatic mutations. Although the majority of them do not confer a growth advantage, some of these non-synonymous passenger mutations may generate neoepitopes that bind avidly to autologous MHC molecules leading to immune recognition and subsequent lymphocyte-mediated tumor cell death. Immunotherapy has now changed treatment paradigms in non-small cell lung cancer (NSCLC), however, the course of immune recognition and adaptive response from premalignancy and early stage disease to advanced metastatic disease has not yet been defined. We hypothesize that tumor-specific immune responses can be documented to evolve throughout the course of the disease. To address this hypothesis we plan the following specific aims: 1) To assess specific immune reactivity in the context of metastatic disease. To this end, we will determine putative neoepitopes by whole exome sequencing and T cell clonality by T cell receptor sequencing in malignant pleural effusions (MPE) from lung cancer patients. The immune contexture will be assessed by flow cytometry. 2) To determine the evolution of neoepitope profiles in the spectrum of disease progression. Here we will assess pulmonary premalignant lesions, the associated primary tumor and MPE from individual patients with recurrent disease following surgery. The immune contexture in each compartment will be assessed. 3) To functionally analyze immune reactivity across the spectrum of disease, we will assess tumor-infiltrating lymphocytes, peripheral blood lymphocytes and MPE lymphocytes for recognition of associated neoepitopes. Understanding the evolution of neoepitope expression and immune reactivity throughout the spectrum of lung cancer initiation and progression will enable the development and informed application of new, effective immunotherapeutic interventions.