Pretreatment tissue TCR repertoire evenness is associated with complete pathologic response in patients with NSCLC receiving neoadjuvant chemoimmunotherapy

Abstract

Purpose: Characterization of the T-cell receptor (TCR) reper- toire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non– small cell lung cancer (NSCLC). Experimental Design: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue sam- ples of 40 patients with NSCLC, 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. Results: We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently 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% confidence interval, 0.897–1.000; P ¼ 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC ¼ 0.767; P ¼ 0.026) or tumor mutational burden (TMB; AUC ¼ 0.550; P ¼ 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selec- tive expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveil- lance, which could explain the high survival rate of these patients. Conclusions: We 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.