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

TGF-beta is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin alpha(V) subunit. The activation of latent TGF-beta by cancer-cell-expressed alpha(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 alpha(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 alpha(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-beta signalling. Thus, our work provides the underlying principle of targeting cancer cell alpha(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 alpha(V) integrin expression leads to better tumour growth control by anti-PD-1 via reduced TGF-beta activation and hence increased infiltration of anti-tumour CD8(+) T cells.