Integrin-α(V)-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade

Ines Malenica (1, 2) , Julien Adam (1, 2) , Stephanie Corgnac (1, 2) , Laura Mezquita (3) , Edouard Auclin (4) , Isabelle Damei (1, 2) , Laetitia Grynszpan (1, 5) , Gwendoline Gros (1) , Vincent de Montpréville (1) , David Planchard (3, 6) , Nathalie Theret (7, 8) , Benjamin Besse (3, 9, 6) , Fathia Mami-Chouaib (1, 2)

1 UMR 1186 - Immunologie intégrative des tumeurs
2 INTIM - Immunologie intégrative des tumeurs et immunothérapie des cancers
3 IGR - Institut Gustave Roussy
4 HEGP - Hôpital Européen Georges Pompidou [APHP]
5 CECJI - Centre d'étude des correspondances et journaux intimes
6 Oncologie thoracique
7 Irset - Institut de recherche en santé, environnement et travail
8 EHESP - École des Hautes Études en Santé Publique [EHESP]
9 Département de médecine oncologique [Gustave Roussy]

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.

Domaines: Sciences du Vivant [q-bio]

Ines Malenica, Julien Adam, Stephanie Corgnac, Laura Mezquita, Edouard Auclin, et al.. Integrin-α(V)-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade. Nature Communications, 2021, 12 (1), pp.5209. ⟨10.1038/s41467-021-25322-y⟩. ⟨hal-03359403⟩