Differential predictive value of resident memory CD8+T cell subpopulations in patients with non-small-cell lung cancer treated by immunotherapy
Authors: Paolini Léa , Tran Thi , Corgnac Stéphanie , Villemin Jean-Philippe , Wislez Marie , Arrondeau Jennifer , Johannes Ludger , Ulmer Jonathan , Vieillard Louis-Victorien , Pineau Joséphine , Gey Alain , Quiniou Valentin , Barennes Pierre , Pham Hang Phuong , Gruel Nadège , Hasan Milena , Libri Valentina , Mella Sebastien , De Percin Sixtine , Boudou-Rouquette Pascaline , Caidi Aziza , Cremer Isabelle , Blons Hélène , Leroy Karen , Laurent-Puig Pierre , De Saint Basile Hortense , Gibault Laure , Ravel Patrice , Mami-Chouaib Fathia , Goldwasser François , Fabre Elizabeth , Damotte Diane , Tartour Eric 
Published: December 2024

BackgroundA high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. In most clinical studies, TRMare defined by the CD103 marker. However, it is clearly established that not all TRMexpress CD103, but can be defined by other markers (CD49a, CD69, etc). The frequency of these subpopulations of TRMexpressing or not CD103 varies according to the location of the cancer. Little is known about their functionality and their predictive impact on response to immunotherapy. In preclinical models, only some subpopulations of TRMare associated with cancer vaccine efficacy.MethodsMultiparametric cytometry analyses were used to demonstrate the presence of TRMsubpopulations in the lung in mice after vaccination and in fresh ex vivo human non-small cell lung cancer (NSCLC). An analysis of the T-cell repertoire of these TRMwas conducted to search for their relationships. Multiplex immunofluorescence techniques were used to quantify intratumor infiltration of TRMsubpopulations in two cohorts of patients with NSCLC. The impact on the clinical outcome of the TRMtumor infiltration was also investigated.ResultsWe identified two main TRMsubpopulations in tumor-infiltrating lymphocytes derived from patients with NSCLC: one co-expressing CD103 and CD49a (double positive (DP)), and the other expressing only CD49a (simple positive (SP)); both exhibiting additional TRMsurface markers like CD69. Despite higher expression of inhibitory receptors, DP TRMexhibited greater functionality compared with SP TRM. Analysis of T-cell receptor (TCR) repertoire and expression of the stemness marker TCF1 revealed shared TCRs between populations, with the SP subset appearing more progenitor-like phenotype. In the training cohort, PD-L1 (Programmed Death-Ligand 1) and TCF1+CD8+T cells predict response to anti-PD-1. In patient with NSCLC validation cohorts, only DP TRMpredicted PD-1 blockade response. Multivariate analysis, including various biomarkers associated with responses to anti-PD-(L)1, such as total CD8, TCF1+CD8+T cells, and PD-L1, showed that only intratumoral infiltration by DP TRMremained significant.ConclusionsThis study highlights the non-equivalence of TRMsubpopulations. The population of TRMco-expressing CD103 and CD49a appears to be the most functional and has the most significant capacity for predicting response to immunotherapy in multivariate analysis in patients with NSCLC.