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

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.

Response to PD-1 checkpoint blockade is unpredictable in lung cancer patients. Here authors show in human lung and mouse tumour models that low or absent α_V integrin expression leads to better tumour growth control by anti-PD-1 via reduced TGF-β activation and hence increased infiltration of anti-tumour CD8⁺ T cells.