The CARM1 Epigenetic Enzyme Inhibits Cross-presenting Dendritic Cell Function in Cancer Immunity [multiome]

The cancer-immunity cycle requires cross-presenting dendritic cells (cDC1) that induce T cell-mediated immunity, but therapeutic strategies for enhancing intratumoral cDC1 function are inadequate. We discovered the epigenetic enzyme Carm1 as a selective negative regulator of cancer antigen presentation by cDC1s, but not cDC2s. Carm1 inactivation promoted cDC1 antigen cross-presentation, activation, and accumulation in tumors; and a Carm1 inhibitor enhanced cDC1-mediated priming of T cells by a cancer vaccine. Carm1 inhibition increased chromatin accessibility at BATF3-JUN and RELA sites critical for cDC1 function and activation. Carm1 expression was regulated by TGF-beta, explaining why Carm1 inactivation enhanced intratumoral cDC1 function without altering cDC1 homeostasis. These studies identify Carm1 as a therapeutic target for enhancing the anti-tumor function of murine and human cDC1.