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

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

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • 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)