2. Academic Validation
  3. Integrin-αV-mediated activation of TGF-β regulates anti-tumour CD8 T cell immunity and response to PD-1 blockade

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

  • Nat Commun. 2021 Sep 1;12(1):5209. doi: 10.1038/s41467-021-25322-y.
Ines Malenica 1,  Julien Adam # 1,  Stéphanie Corgnac # 1,  Laura Mezquita 2 3 4,  Edouard Auclin 5,  Isabelle Damei 1,  Laetitia Grynszpan 1,  Gwendoline Gros 1,  Vincent de Montpréville 1 6,  David Planchard 2,  Nathalie Théret 7,  Benjamin Besse 2,  Fathia Mami-Chouaib 8
Affiliations

Affiliations

  • 1 INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Médecine-Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.
  • 2 Department of Cancer Medicine, Gustave Roussy Cancer Campus, Institut d'Oncologie Thoracique, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 3 Laboratory of Translational Genomics and Targeted Therapeutics in Solid Tumours, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
  • 4 Medical Oncology Department, Hospital Clínic, Barcelona, Spain.
  • 5 Medical and Thoracic Oncology Department, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • 6 Hôpital Marie-Lannelongue, Service d'Anatomie Pathologique, Le-Plessis-Robinson, France.
  • 7 Univ Rennes, Inserm, EHESP, Irset-UMR-S1085, Rennes, France.
  • 8 INSERM UMR 1186, Integrative Tumour Immunology and Immunotherapy, Gustave Roussy, Fac. de Médecine-Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France. fathia.mami-chouaib@gustaveroussy.fr.
  • # Contributed equally.
PMID: 34471106 DOI: 10.1038/s41467-021-25322-y
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.

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