Integrin-αV-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade
Ines Malenica, Julien Adam, Stéphanie Corgnac, Laura Mezquita, Édouard Auclin, Isabelle Damei, Laetitia Grynszpan, Gwendoline Gros, Vincent de Montpréville, David Planchard, Nathalie Théret, Benjamin Besse, Fathia Mami‐Chouaib
Abstract
Abstract TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin α V subunit. The activation of latent TGF-β by cancer-cell-expressed α V 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 α V is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8 + CD103 + tumour-infiltrating lymphocytes. Mechanistically, tumour α V 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 α V for more efficient PD-1 checkpoint blockade therapy.