Abstract
KRASG12D drives MDSC-mediated resistance to immune checkpoint blockade in patients with colorectal cancer.
Major finding: KRASG12D drives MDSC-mediated resistance to immune checkpoint blockade in patients with colorectal cancer.
Mechanism: KRASG12D-mediated repression of IRF2 promotes the activation of CXCL3–CXCR2 signaling in MDSCs.
Impact: Enhancing IRF2 expression or CXCR2 blockade may overcome immunotherapy resistance in patients with colorectal cancer.
To ascertain how oncogenic KRAS drives immunosuppression in colorectal cancer, Liao and colleagues performed immunophenotyping of colon tumors from mice that harbored conditional null alleles of Apc and Trp53−/− (iAP) or iAP mice that harbored doxycycline-inducible KrasG12D (iKAP). Compared to iAP tumors, iKAP tumors exhibited a more immunosuppressive microenvironment that was characterized by decreased T-cell infiltration and increased myeloid-derived suppressor cell (MDSC) infiltration; further, the loss of KRASG12D expression via doxycycline withdrawal resulted in increased T-cell infiltration and decreased MDSC infiltration. Pathway analysis of RNA-sequencing profiles showed that genes associated with IFNα/γ signaling, particularly IRF2, were the most significantly repressed in iKAP tumors and cell lines compared to iAP tumors and cell lines. Consistent with these findings, IRF2 expression was low or negative in KRAS-positive areas in iKAP tumors, and doxycycline withdrawal resulted in the concomitant loss of KRASG12D expression and increased IRF2 expression; similarly, mutant KRAS and IRF2 deletion were mutually exclusive in human colorectal cancer. Moreover, IRF2 overexpression in iKAP cells resulted in increased IFNα/γ signaling and decreased MDSC migration. Integrated cytokine and IRF2 chromatin immunoprecipitation sequencing analyses showed that enforced IRF2 expression resulted in increased binding of IRF2 to IRF2-binding elements in the promoter of Cxcl3, which is a CXCR2 ligand, and suppression of CXCL3 or KRAS expression resulted in decreased CXCL3 expression and secretion. Expression of CXCR2, which drives MDSC migration, was colocalized with MDSCs in iKAP tumors; similarly, MDSC migration was induced by exogenous CXCL3 or decreased upon treatment with the CXCR2 inhibitor SX-682 or a CXCL3-neutralizing antibody. In vivo, IRF2 overexpression or SX-682 increased the levels of tumor-infiltrating cytotoxic lymphocytes and the efficacy of PD-1 blockade. In preliminary studies, patients with IRF2-positive colorectal cancer exhibited increased responsiveness to anti–PD-1 therapy. These findings characterize the role of oncogenic KRAS in immunosuppression and identify a potential immunotherapy strategy.
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