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

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 Chakravarti, Andrew Chang, Denise J. Spring, Qing ChangJianhua Zhang, Dipen M. Maru, Dean Y. Maeda, John A. Zebala, Scott Kopetz, Y. Alan Wang*, Ronald A. DePinho

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

Abstract

The biological functions and mechanisms of oncogenic KRAS G12D (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.

Original languageEnglish (US)
Pages (from-to)559-572.e7
JournalCancer Cell
Volume35
Issue number4
DOIs
StatePublished - Apr 15 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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