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Cancer Cell. 2019 Apr 15;35(4):559-572.e7. doi: 10.1016/j.ccell.2019.02.008. Epub 2019 Mar 21.

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

Author information

1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China.
2
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
4
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Syntrix Pharmaceuticals, Auburn, WA 98001, USA.
8
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: yalanwang@mdanderson.org.
9
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.

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.

KEYWORDS:

CXCL3; CXCR2; IRF2; KRAS; anti-PD-1; colorectal cancer (CRC); immune checkpoint blockade (ICB)

PMID:
30905761
PMCID:
PMC6467776
[Available on 2020-04-15]
DOI:
10.1016/j.ccell.2019.02.008

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