KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer

• DOI: 10.1016/j.ccell.2019.02.008
• Publication Date: 2019-03-21T14:43:34Z
• Authors: Wenting Liao; Michael J. Overman; Adam T. Boutin; Xiaoying Shang; Di Zhao; Prasenjit Dey; Jiexi Li; Guocan Wang; Zhengdao Lan; Jun Li; Ming Tang; Shan Jiang; Xingdi Ma; Peiwen Chen; Riham Katkhuda; Krittiya Korphaisarn; Deepavali Chakrav...; Andrew Chang; Denise J. Spring; Qing Chang; Jianhua Zhang; Dipen M. Maru; Dean Y. Maeda; John A. Zebala; Scott Kopetz; Y. Alan Wang; Ronald A. DePinho
• Keywords: Adult; Male; 0303 health sciences; Adenomatous Polyposis Coli Protein; Mice, Transgenic; Mice, SCID; Middle Aged; 3. Good health; Gene Expression Regulation, Neoplastic; Mice, Inbred C57BL; 03 medical and health sciences; Antineoplastic Agents, Immunological; Cell Movement; Drug Resistance, Neoplasm; Mice, Inbred NOD; Cell Line, Tumor; Animals; Humans; Female; Colorectal Neoplasms; Chemokines, CXC; Interferon Regulatory Factor-2; Aged

The biological functions and mechanisms of oncogenic KRASG12D (KRAS∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.