CARM1 Inhibition Enhances Cytotoxic T-cell Function and Sensitizes Resistant Cancers to Immune Attack

Several cancer drugs activate innate immune pathways in tumor cells but unfortunately compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme, elicited beneficial effects in both cytotoxic T cells and tumor cells. Carm1 inactivation in cytotoxic T cells enhanced their activation state and anti-tumor function. In contrast, Carm1 inhibition in tumor cells resulted in genomic damage and activation of the cGAS-STING pathway. Inactivation of Med12, a regulatory component of the Mediator complex, elicited the same tumor cell phenotype, thereby connecting Carm1 to regulation of transcription. Inhibition of Carm1 induced potent T cell mediated tumor immunity and sensitized resistant, highly aggressive tumor cells to checkpoint blockade. The Carm1 – Med12 pathway thus offers an opportunity to enhance anti-tumor immunity while simultaneously sensitizing resistant tumor cells to immune attack. Overall design: Characterization of mRNA and RNA:DNA hybrid structures in wild-type and carm1 knockout B16-F10 cells using polyA RNA-seq and sDRIP-seq.