LAUSR

The precise biologic functions and mechanisms of oncogenic KrasG12D (Kras*) in therapeutic resistance, including immune therapy, are not understood. Here, utilizing a colorectal cancer (CRC) mouse model engineered with an inducible Kras* transgene and conditional null APC and Trp53 alleles (iKAP) that we recently established (Boutin et al., Gene & Development 2017), we observed that KRAS*-expressing invasive tumors possess a prominent immune-suppressive profile characterized by a preponderance of myeloid-derived suppressor cells (MDSCs). Integrated transcriptomic and genomic analyses identified the Interferon Regulatory Factor 2 (IRF2) gene as a key downstream target of KRAS* mediating tumor progression and immune suppression. Mechanistically, integrated transcriptomics, cytokine profiling and ChIP-seq analysis identified CXCL3 as a key direct target of IRF2, and pharmacologic inhibition of CXCL3 or its receptor CXCR2 resulted in suppression of MDSC migration and infiltration in KRAS*-expressing CRC tumors. Translational studies established that de novo anti-PD1 resistance of KRAS*-expressing tumors can be overcome by enforced IRF2 expression or by treatment with small-molecule CXCR2 antagonist SX-682. Correspondingly, CRC patient tumors with higher IRF2 expression show increased response to anti-PD1 therapy. This KRAS*-mediated immune suppressive mechanism provides a framework for patient selection and combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in advanced CRC. Citation Format: Wenting Liao, Michael Overman, Adam Boutin, Scott Kopetz, Ron DePinho, Alan Wang. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B52.