Abstract 69: A biological circuit involving Mef2c, Mef2d and Hdac9 controls the immunosuppressive functions of CD4+Foxp3+ T-regulatory cells and anti-cancer immunity

The Mads/Mef2 (Mef2a/b/c/d) transcription factors (TFs) regulate differentiation of myocytes, neurons and hematopoietic cells. Mef2 TFs are subject to regulation by negative feedback in that they promote transcription of their strong repressor Hdac9, providing temporal control of Mef2-driven differentiative responses. Disruption of this feedback occurs within various sarcomas and leukemias. In addition, Mef2 TFs indirectly control tumor progression by regulating antitumor immunity. We recently reported that in CD4+CD25+Foxp3+ T-regulatory (Treg) cells, Mef2d is required for the acquisition of an effector Treg phenotype and the activation of an epigenetic program that in turn represses the anti-cancer responses of CD4, CD8 and B-cells. We now report that similarly to Mef2d, deletion of Mef2c in Tregs switches off expression of Il10 and Ctla4 and leads to enhanced antitumor immunity in syngeneic models of lung cancer. Mechanistically, Mef2c does not directly bind to the regulatory elements of Ctla4 and Il10, but rather, its loss-of-function in Tregs induces the expression of the transcriptional repressor Hdac9. As a consequence, Mef2d, the more abundant member of the Mef2 family, is displaced from p300 and is converted by Hdac9 into a transcriptional repressor at these loci. This leads to the impairment of Treg suppressive properties and to enhanced anti-cancer immunity. These data further highlight the central role played by Mef2/Hdac9 axis in the regulation of CD4+Foxp3+ Treg function and provide a rationale for the development of small molecules targeting Mef2 and/or Mef2-containing complexes. Citation Format: Eros Di Giorgio, Liqing Wang, Yan Xiong, Rongxiang Han, Arabinda Samanta, Matteo Trevisanut, Wayne W. Hancock. A biological circuit involving Mef2c, Mef2d and Hdac9 controls the immunosuppressive functions of CD4+Foxp3+ T-regulatory cells and anti-cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 69.