Immunogenomic determinants of response and resistance to neoadjuvant anti-PD-1 in resectable NSCLC

Summary More than 1.8 million people worldwide are diagnosed with non-small cell lung cancer (NSCLC) every year. Of these patients, 20% present with stage I or II disease. For these patients, surgical resection remains the first course of treatment, however even in apparently curative surgery 50% of stage I and 70% of stage II NSCLC patients will recur and eventually die of the disease. Neoadjuvant and adjuvant chemotherapy are standard treatments for resectable NSCLC and are used with the dual goals of reducing tumor size prior to surgery and preventing relapse. We recently completed a clinical trial of neoadjuvant PD-1 blockade in resectable NSCLC and demonstrated an impressive 45% major pathologic response rate. To date, however, the mechanisms underlying response to this treatment are unknown. In the study proposed here, we will leverage this existing clinical trial and the biospecimens already obtained to elucidate the functional impact of PD-1 blockade on tumor-reactive T cells and to determine how differential T cell transcriptional programs facilitate pathologic response. We will implement a novel approach, using the T cell receptor as a molecular barcode for antigen-specificity using basic and single cell sequencing technologies, to understand the dynamic interplay of different T cell subsets and how their transcriptional programming is modified by anti- PD-1. Identification of targetable markers of response or resistance, development of novel bioinformatic approaches to analyze neoantigen-specific single cell data, and enumeration of immunogenomic determinants of pathologic response to neoadjuvant PD-1 blockade are only some of the key outcomes of this study.