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

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.

• 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 Chakravarti, 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
• Journal: Cancer cell (Cancer Cell) Vol. 35 Issue 4 Pg. 559-572.e7 (04 15 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 30905761 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Adenomatous Polyposis Coli Protein
• Antineoplastic Agents, Immunological
• Chemokines, CXC
• Cxcl3 protein, mouse
• Interferon Regulatory Factor-2
• Irf2 protein, mouse
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• Receptors, Interleukin-8B
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• adenomatous polyposis coli protein, mouse
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Adenomatous Polyposis Coli Protein (genetics, metabolism)
• Adult
• Aged
• Animals
• Antineoplastic Agents, Immunological (pharmacology)
• Cell Line, Tumor
• Cell Movement
• Chemokines, CXC (metabolism)
• Colorectal Neoplasms (drug therapy, genetics, immunology, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Interferon Regulatory Factor-2 (genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Middle Aged
• Myeloid-Derived Suppressor Cells (drug effects, immunology, metabolism)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Receptors, Interleukin-8B (metabolism)
• Signal Transduction
• Tumor Escape
• Tumor Microenvironment
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Young Adult