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

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.