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

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-CX

SUBMITTER: Liao W 

PROVIDER: S-EPMC6467776 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature