MEF2D regulates T-cell function via CD70-CD27 signaling and promotes immune evasion in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) stands as one of the most prevalent and fatal malignancies globally, posing a persistent challenge in its treatment due to immune evasion. We knocked down MEF2D in HCC cell lines and analyzed HCC tissues and cell lines by RNA sequencing, Western blot, and immunohistochemistry. Chromatin immunoprecipitation was used to analyze the regulation of CD70 transcription by MEF2D. HCC cells with or without MEF2D knockout were injected into the livers of syngeneic BALB/c mice. Flow cytometry was used to analyze the function of T cells in tumors, spleens, and lymph nodes. We found that in contrast to wild-type tumors in immunocompetent mice, HCC with MEF2D knockdown had smaller tumors, increased T-cell activation, and impaired T regulatory (Treg) cell suppressive function. Mechanistically, MEF2D bound to the promoter region of CD70 gene and activated its transcription and this process was further enhanced by p300-induced MEF2D acetylation. CD70 blocking antibody inhibited activation of the CD70-CD27 signaling axis in murine HCC tumors, leading to impaired immunosuppressive function of Tregs and enhanced antitumor immunity. MEF2D blocks T-cell–mediated antitumor immunity by regulating the expression of CD70 and activating the CD70-CD27 signaling axis. Strategies to manipulate this pathway may improve the efficacy of liver cancer immunotherapy.