CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor Cells and T Cells.
CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor Cells and T Cells.
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DOI：
10.1158/2159-8290.cd-20-1144
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发表时间：
2021-08
期刊：
影响因子：
28.2
通讯作者：
Wucherpfennig KW
中科院分区：
文献类型：
--
作者：
Kumar S;Zeng Z;Bagati A;Tay RE;Sanz LA;Hartono SR;Ito Y;Abderazzaq F;Hatchi E;Jiang P;Cartwright ANR;Olawoyin O;Mathewson ND;Pyrdol JW;Li MZ;Doench JG;Booker MA;Tolstorukov MY;Elledge SJ;Chédin F;Liu XS;Wucherpfennig KW
A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise anti-tumor immune function. We discovered that inhibition of Carm1, an epigenetic enzyme and co-transcriptional activator, elicited beneficial anti-tumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their anti-tumor function and preserved memory-like populations required for sustained anti-tumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells and NK cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of Carm1 with a small molecule elicited potent anti-tumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this co-transcriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack.
