Journal
CANCER CELL
Volume 35, Issue 4, Pages 559-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2019.02.008
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Funding
- NIH, United States [R01 CA084628, PO1 CA117969]
- MD Anderson Colorectal Cancer Moon Shot funds, United States
- National Basic Research Program of China (973 program), China [2015CB554002]
- National Natural Science Foundation of China, China [81672886, 81773101, 81872401]
- Triumph postdoctoral program at MD Anderson by CPRIT, United States [RP170067]
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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.
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