| Literature DB >> 30905761 |
Wenting Liao1, Michael J Overman2, Adam T Boutin3, Xiaoying Shang3, Di Zhao3, Prasenjit Dey3, Jiexi Li3, Guocan Wang3, Zhengdao Lan3, Jun Li4, Ming Tang4, Shan Jiang3, Xingdi Ma3, Peiwen Chen3, Riham Katkhuda5, Krittiya Korphaisarn2, Deepavali Chakravarti3, Andrew Chang3, Denise J Spring3, Qing Chang6, Jianhua Zhang4, Dipen M Maru5, Dean Y Maeda7, John A Zebala7, Scott Kopetz2, Y Alan Wang8, Ronald A DePinho9.
Abstract
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.Entities:
Keywords: CXCL3; CXCR2; IRF2; KRAS; anti-PD-1; colorectal cancer (CRC); immune checkpoint blockade (ICB)
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Year: 2019 PMID： 30905761 PMCID： PMC6467776 DOI： 10.1016/j.ccell.2019.02.008
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743