Platelet-derived microparticles adoptively transfer integrin β3 to promote antitumor effect of tumor-infiltrating T cells

Abstract

ABSTRACTApproximately two-thirds of hepatocellular carcinoma (HCC) is considered a “cold tumor” characterized by few tumor-infiltrating T cells and an abundance of immunosuppressive cells. Cilengitide, an integrin αvβ3 inhibitor, has failed in clinical trials as a potential anticancer drug. This failure implies that integrin αvβ3 may play an important role in immune cells. However, the expression and potential role of integrin αvβ3 in T cells of HCC patients remain unknown. Here, we established two HCC models and found that cilengitide had a dual effect on the HCC microenvironment by exerting both antitumor effect and immunosuppressive effect on T cells. This may partly explain the failure of cilengitide in clinical trials. In clinical specimens, HCC-infiltrating T cells exhibited deficient expression and activation of integrin β3, which was associated with poor T-cell infiltration into tumors. Additionally, integrin β3 functioned as a positive immunomodulatory molecule to facilitate T-cell infiltration and T helper 1-type immune response in vitro. Furthermore, T cells and platelet-derived microparticles (PMPs) co-culture assay revealed that PMPs adoptively transferred integrin β3 to T cells and positively regulated T cell immune response. This process was mediated by clathrin-dependent endocytosis and macropinocytosis. Our data demonstrate that integrin β3 deficiency on HCC-infiltrating T cells may be involved in shaping the immunosuppressive tumor microenvironment. PMPs transfer integrin β3 to T cells and positively regulate T cell immune response, which may provide a new insight into immune therapy of HCC.

Keywords

• Hepatocellular carcinoma
• integrin αvβ3
• platelet-derived microparticles
• tumor-infiltrating lymphocytes