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, Edouard Auclin, Isabelle Damei, Laetitia Grynszpan, Gwendoline Gros, Vincent Montpréville, David Planchard, Nathalie Théret, Benjamin Besse and Fathia Mami-Chouaib ()
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Ines Malenica: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
Julien Adam: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
Stéphanie Corgnac: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
Laura Mezquita: Université Paris-Saclay
Edouard Auclin: Hôpital Européen Georges Pompidou, AP-HP
Isabelle Damei: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
Laetitia Grynszpan: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
Gwendoline Gros: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
Vincent Montpréville: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay
David Planchard: Université Paris-Saclay
Nathalie Théret: Univ Rennes, Inserm, EHESP, Irset-UMR-S1085
Benjamin Besse: Université Paris-Saclay
Fathia Mami-Chouaib: Fac. de Médecine—Univ. Paris-Sud, Université Paris-Saclay

Nature Communications, 2021, vol. 12, issue 1, 1-16

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 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.

Date: 2021
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DOI: 10.1038/s41467-021-25322-y

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