TCR repertoire sequencing of 254 resected non-small cell lung cancers to reveal TCR clonality in normal tissues compared to tumor tissues.

Abstract

11500 Background: The mechanisms underlying resistance to immune checkpoint blockade are poorly understood. Major efforts have been made to understand how mutations, through generation of neoantigens, may alter tumor immunogenicity and anti-tumor responses, particularly through T cell responses. However, the T cell repertoire and its interaction with cancers bearing specific molecular alterations have not been systemically studied. Methods: We delineated the landscapes in the T cell receptor (TCR) repertoire, immune infiltration (immunohistochemistry using multiple immune markers), genome (exome sequencing), epigenome (methylation array) and transcriptome (mRNA gene expression array) of 254 resected non-small cell lung cancers (NSCLC), matched normal lung tissues and peripheral blood mononuclear cells (PBMC). We report herein the preliminary analyses of TCR sequencing of NSCLC tumors and matched normal lung tissues. Results: We observed that: 1) Smaller tumors (smaller than median) had a higher T cell infiltrate (p = 0.0016) and higher entropy than larger tumors (p = 0.0098); 2) Tumors from ever/current smokers had higher T cell clonality than former/never-smokers (p = 0.005); 3) TCR clonality was positively correlated with mutational burden (p = 0.0026); 4) Compared to tumors, normal lung tissues demonstrated significantly less T cell infiltration (p = 2.1x10^-11), but a significantly higher clonality (p = 3.9x10^-7). Finally, many T cell clones, including major clones were shared between normal lung tissues and matched NSCLC tumors. Conclusions: Our preliminary data demonstrate the distinct immune microenvironment in different NSCLC tumors may be associated with particular clinicopathological features. The higher TCR clonality in normal lung tissues and overlap of T cell clones between normal lung and NSCLC tumors implies a significant proportion of tumor infiltrating T cells may be a function of constant exposure to mutagens rather than an anti-tumor response. Analysis of the peripheral TCR repertoire, the molecular landscape of these tumors and the association with immune profiling is underway.