The CARM1 epigenetic enzyme inhibits cross-presenting dendritic cell function in cancer immunity
Abstract
The cancer-immunity cycle requires cross-presenting type I conventional dendritic cells (cDC1s) that induce T cell–mediated immunity, but therapeutic strategies for enhancing intratumoral cDC1 function are currently inadequate. We found the epigenetic enzyme CARM1 (coactivator-associated arginine methyltransferase 1) to be a selective negative regulator of cancer antigen presentation by cDC1s but not cDC2s. Inactivation of the Carm1 gene promoted cDC1 antigen cross-presentation, activation, and accumulation in tumors, and a CARM1 inhibitor enhanced cDC1-mediated priming of T cells by means of a cancer neoantigen vaccine. CARM1 inhibition increased chromatin accessibility at BATF3-Jun and RelA sites that are critical for cDC1 function and activation. Transforming growth factor–β regulated Carm1 expression, which suggests that CARM1 inactivation enhanced intratumoral cDC1 function without altering cDC1 homeostasis. These studies identify CARM1 as a potential therapeutic target for enhancing the antitumor function of mouse and human cDC1s.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (18)
Xixi Zhang
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Sherin Xirenayi
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ye Zhao
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Wen Wang
Yuyang Han
Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Miguel Sobral
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Shawn Kang
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Chi Zhang
Graham L. Barlow
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jason Pyrdol
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jae-Won Cho
Gene Lay Institute of Immunology and Inflammation, Brigham and Women’s Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Kun Huang
Molecular Imaging Core, Dana-Farber Cancer Institute, Boston, MA, USA.
Xiaohan Ning
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
Martin Hemberg
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Guo-Cheng Yuan
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Eliezer M. Van Allen
David J. Mooney
Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Kai W. Wucherpfennig
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.