Using tumor specimens from patients with NSCLC, Malenica et al. showed that lower αv levels were associated with better anti-PD-1 axis-related PFS and increased density of CD103+CD8+ TRM TILs. Ex vivo, tumor-expressed αv integrins contributed to activation of TGF-β to induce CD103 expression on activated CD8+ T cells. In mouse modeling, αv ablation from tumor cells increased activated PD-1+Ki-67+ KLRG1+CD8+ T cells and correlated with decreased active TGFβ intratumorally. PD-1 blockade improved control of αv knockout tumors and increased granzyme B+CD69+CD103+CD8+ TRM TILs; this was inhibited by intratumoral CD103 blockade.
Contributed by Paula Hochman
ABSTRACT: TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin αV subunit. The activation of latent TGF-β by cancer-cell-expressed αV re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell αV is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8+CD103+ tumour-infiltrating lymphocytes. Mechanistically, tumour αV regulates CD8 T cell recruitment, induces CD103 expression on activated CD8+ T cells and promotes their differentiation to granzyme B-producing CD103+CD69+ resident memory T cells via autocrine TGF-β signalling. Thus, our work provides the underlying principle of targeting cancer cell αV for more efficient PD-1 checkpoint blockade therapy.
Author Info: (1) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (2) INSERM UMR 118
Author Info: (1) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (2) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (3) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (4) Department of Cancer Medicine, Gustave Roussy Cancer Campus, Institut d'Oncologie Thoracique, Gustave Roussy, Universit Paris-Saclay, Villejuif, France. Laboratory of Translational Genomics and Targeted Therapeutics in Solid Tumours, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain. Medical Oncology Department, Hospital Clnic, Barcelona, Spain. (5) Medical and Thoracic Oncology Department, Hpital Europen Georges Pompidou, AP-HP, Paris, France. (6) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (7) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (8) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. (9) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. Hpital Marie-Lannelongue, Service d'Anatomie Pathologique, Le-Plessis-Robinson, France. (10) Department of Cancer Medicine, Gustave Roussy Cancer Campus, Institut d'Oncologie Thoracique, Gustave Roussy, Universit Paris-Saclay, Villejuif, France. (11) Univ Rennes, Inserm, EHESP, Irset-UMR-S1085, Rennes, France. (12) Department of Cancer Medicine, Gustave Roussy Cancer Campus, Institut d'Oncologie Thoracique, Gustave Roussy, Universit Paris-Saclay, Villejuif, France. (13) INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Mdecine-Univ. Paris-Sud, Universit Paris-Saclay, Villejuif, France. fathia.mami-chouaib@gustaveroussy.fr.
