(1) Paolini L (2) Tran T (3) Corgnac S (4) Villemin JP (5) Wislez M (6) Arrondeau J (7) Johannes L (8) Ulmer J (9) Vieillard LV (10) Pineau J (11) Gey A (12) Quiniou V (13) Barennes P (14) Pham HP (15) Gruel N (16) Hasan M (17) Libri V (18) Mella S (19) De Percin S (20) Boudou-Rouquette P (21) Caidi A (22) Cremer I (23) Blons H (24) Leroy K (25) Laurent-Puig P (26) De Saint Basile H (27) Gibault L (28) Ravel P (29) Mami-Chouaib F (30) Goldwasser F (31) Fabre E (32) Damotte D (33) Tartour E

Journal for immunotherapy of cancer

BACKGROUND: A high density of resident memory T cells (T(RM)) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. In most clinical studies, T(RM) are defined by the CD103 marker. However, it is clearly established that not all T(RM) express CD103, but can be defined by other markers (CD49a, CD69, etc). The frequency of these subpopulations of T(RM) expressing 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 T(RM) are associated with cancer vaccine efficacy. METHODS: Multiparametric cytometry analyses were used to demonstrate the presence of T(RM) subpopulations 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 T(RM) was conducted to search for their relationships. Multiplex immunofluorescence techniques were used to quantify intratumor infiltration of T(RM) subpopulations in two cohorts of patients with NSCLC. The impact on the clinical outcome of the T(RM) tumor infiltration was also investigated. RESULTS: We identified two main T(RM) subpopulations 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 T(RM) surface markers like CD69. Despite higher expression of inhibitory receptors, DP T(RM) exhibited greater functionality compared with SP T(RM). 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 T(RM) predicted 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 T(RM) remained significant. CONCLUSIONS: This study highlights the non-equivalence of T(RM) subpopulations. The population of T(RM) co-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.

Author Info: (1) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. (2) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. (3) INSERM UMR1186, Gustave Roussy,

Author Info: (1) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. (2) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. (3) INSERM UMR1186, Gustave Roussy, Fac.de Medecine-Univ Paris-Sud, UniversitŽ Paris-Saclay, Villejuif, France, INSERM, Villejuif, France. (4) INSERM U1194, Institut de Recherche en CancŽrologie de Montpellier, Montpellier, France. (5) Service de Pneumologie Hopital Cochin, UniversitŽ de Paris, Paris, France. Centre de recherche des Cordeliers, Universite Paris CitŽ, Sorbonne UniversitŽ, INSERM UMRS1138, Paris, France. (6) Department of Medical Oncology, UniversitŽ Paris CitŽ, Cochin Hospital, APHP, Paris, France. (7) Cellular and Chemical Biology Unit, Institut Curie, Paris, France. (8) Cellular and Chemical Biology Unit, Institut Curie, Paris, France. (9) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. (10) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. Department Immunology, H™pital EuropŽen Georges Pompidou, Hopital Necker, APHP, Paris, France. (11) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. Department Immunology, H™pital EuropŽen Georges Pompidou, Hopital Necker, APHP, Paris, France. (12) Parean Biotech, Saint Malo, France. (13) Parean Biotech, Saint Malo, France. (14) Parean Biotech, Saint Malo, France. (15) Diversity and plasticity of childhood tumours lab, INSERM U830 Equipe LabellisŽe Ligue National contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France. Department of translational research, PSL Research University, Institut Curie Research Center, Paris, France. (16) Cytometry and Biomarkers UTechs, Center for translational Science, Institut Pasteur, Paris, France. (17) Cytometry and Biomarkers UTechs, Center for translational Science, Institut Pasteur, Paris, France. (18) Cytometry and Biomarkers UTechs, Center for translational Science, Institut Pasteur, Paris, France. (19) Department of Medical Oncology, UniversitŽ Paris CitŽ, Cochin Hospital, APHP, Paris, France. (20) Department of Medical Oncology, UniversitŽ Paris CitŽ, Cochin Hospital, APHP, Paris, France. (21) INSERM UMR1186, Gustave Roussy, Fac.de Medecine-Univ Paris-Sud, UniversitŽ Paris-Saclay, Villejuif, France, INSERM, Villejuif, France. (22) Centre de recherche des Cordeliers, Universite Paris CitŽ, Sorbonne UniversitŽ, INSERM UMRS1138, Paris, France. (23) Centre de recherche des Cordeliers, Universite Paris CitŽ, Sorbonne UniversitŽ, INSERM UMRS1138, Paris, France. Biochimie, Hopital EuropŽen Georges Pompidou, Paris, France. (24) Centre de recherche des Cordeliers, Universite Paris CitŽ, Sorbonne UniversitŽ, INSERM UMRS1138, Paris, France. Biochimie, Hopital EuropŽen Georges Pompidou, Paris, France. (25) Centre de recherche des Cordeliers, Universite Paris CitŽ, Sorbonne UniversitŽ, INSERM UMRS1138, Paris, France. Biochimie, Hopital EuropŽen Georges Pompidou, Paris, France. Paris Cancer Institute Carpem, Paris, France. (26) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. (27) Department Pathology, H™pital EuropŽen Georges Pompidou, Paris, France. (28) INSERM U1194, Institut de Recherche en CancŽrologie de Montpellier, Montpellier, France. (29) INSERM UMR1186, Gustave Roussy, Fac.de Medecine-Univ Paris-Sud, UniversitŽ Paris-Saclay, Villejuif, France, INSERM, Villejuif, France. (30) Department of Medical Oncology, UniversitŽ Paris CitŽ, Cochin Hospital, APHP, Paris, France. (31) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France. Onco-pneumology, Hopital EuropŽen Georges Pompidou, Paris, France. (32) Centre de recherche des Cordeliers, Universite Paris CitŽ, Sorbonne UniversitŽ, INSERM UMRS1138, Paris, France. Departments of Pathology Hospital Cochin Assistance Publique Hopitaux de Paris, APHP, Paris, France. Department of Pathology, Hopital Cochin, APHP, Paris, France. (33) UniversitŽ Paris CitŽ, INSERM, PARCC, Paris, France, Paris, France eric.tartour@aphp.fr. Department Immunology, H™pital EuropŽen Georges Pompidou, Hopital Necker, APHP, Paris, France.

Citation: J Immunother Cancer 2024 Dec 3 12: Epub12/03/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39631852

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