Pre-treatment tissue TCR repertoire evenness is associated with complete pathological response in patients with NSCLC receiving neoadjuvant chemoimmunotherapy.

Abstract

PURPOSE\nCharacterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathological response to immunotherapy in locally-advanced non-small cell lung cancer (NSCLC).\n\n\nEXPERIMENTAL DESIGN\nIn this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 NSCLC patients, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined.\n\n\nRESULTS\nWe have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequent-ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% CI, 0.897 to 1.000; p=0.001), and improving the results of PD-L1 TPS (AUC 0.767; p=0.026) or TMB (AUC 0.550; p=0.687). Furthermore, tumors with high pre-treatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pre-treatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients.\n\n\nCONCLUSIONS\nWe have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance.