Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy

Abstract

AbstractA high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. However, in preclinical models, only some subpopulations of TRMare associated with cancer vaccine efficacy.We identified two main TRMsubpopulations in tumor-infiltrating lymphocytes derived from non-small cell lung cancer (NSCLC) patients: one co-expressing CD103 and CD49a (DP), and the other expressing only CD49a (MP); both exhibiting additional TRMsurface markers like CD69. DP TRMexhibited greater functionality compared to MP TRM. Analysis of T-cell receptor (TCR) repertoire and of the stemness marker TCF-1 revealed shared TCRs between populations, with the MP subset appearing more progenitor-like phenotype. In two NSCLC patient cohorts, only DP TRMpredicted PD-1 blockade response. Multivariate analysis, including various biomarkers (CD8, TCF1+CD8+T cells, and PD-L1) associated with responses to anti-PD(L)1, showed that only intra-tumoral infiltration by DP TRMremained significant. This study highlights the non-equivalence of TRMpopulations and emphasizes the importance of distinguishing between them to better define their role in antitumor immunity and as a biomarker of response to immunotherapy.