RNF8 enhances the sensitivity of PD-L1 inhibitor against melanoma through ubiquitination of galectin-3 in stroma

Abstract

The failure of melanoma immunotherapy can be mediated by immunosuppression in the tumor microenvironment (TME) and insufficient activation effector T cells to against tumor. Here, we show that inhibition of galectin-3 (gal-3) enhances the infiltration of T cells in TME and improves the sensitivity of anti-PD-L1 therapy. We identify that RNF8 downregulated the expression of gal-3 by K48-polyubiquitination and promoted gal-3 degradation via ubiquitin proteasome system. RNF8 deficiency in host but sufficiency in implanted melanoma results immune exclusion and tumor progression due to up-regulation of gal-3. Up-regulation of gal-3 decreased the immune cell infiltration by restricting IL-12 and IFN-γ. Inhibition of gal-3 reverses immunosuppression and induces immune cells infiltration in tumor microenvironment. Moreover, gal-3 inhibitor treatment can increase the sensitivity of PD-L1 inhibitors via increasing immune cells infiltration and enhancing immune response in tumor. This study reveals a previously unrecognized immunoregulation function of RNF8 and provides a promising strategy for therapy of “cold” tumors. Tremendous effects of melanoma treatment can be achieved by facilitating immune cell infiltration combined with anti-PD-L1 treatment.