Using a colorectal cancer (CRC) mouse model with an inducible oncogenic Kras allele, Liao et al. found that mutated KRAS inhibits antitumor immunity by suppressing the expression of IRF2 (a repressor of Cxcl3 expression). With low or no IRF2 expression, cancer cells express high levels of CXCL3, which recruits MDSCs to the tumor via CXCR2. Enforcing IRF2 expression reduced CXCL3 expression, MDSC infiltration, and tumor growth. Inhibiting the CXCL3-CXCR2 axis overcame resistance to anti-PD-1. Analysis of human CRC samples aligned with this mechanism, and higher IRF2 levels correlated with response to anti-PD-1 in a small cohort.
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-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.
Author Info: (1) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, Nanfang Hospital, Southern Medical University,
Author Info: (1) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, Guangdong, China. (2) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (3) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (4) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (5) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (6) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (7) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (8) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (9) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (10) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (11) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (12) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (13) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (14) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (15) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (16) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (17) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (18) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (19) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (20) Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (21) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (23) Syntrix Pharmaceuticals, Auburn, WA 98001, USA. (24) Syntrix Pharmaceuticals, Auburn, WA 98001, USA. (25) Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (26) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: yalanwang@mdanderson.org. (27) Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.
