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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.

SUBMITTER: Liao W 

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

REPOSITORIES: biostudies-literature

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The biological functions and mechanisms of oncogenic KRAS<sup>G12D</sup> (KRAS<sup>∗</sup>) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS<sup>∗</sup> represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS<sup>∗</sup>-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration t  ...[more]

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