Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes.

ABSTRACT: RAS-MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKis) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38 MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the antitumor immune response. This compensatory response also results in decreased sensitivity toward MAPKi, and, accordingly, combining anti-CD73 antibodies and MAPKi significantly enhances the antitumor effect compared to single-agent treatment in vivo. Combini

SUBMITTER: Terp MG 

PROVIDER: S-EPMC8637576 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature