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KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer
Open accessAbstract
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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“In colon cancer, mutant KRAS has been shown to inhibit expression of interferon regulatory factor2 (IRF2), which is required for interferon-mediated immune responses [69].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [69]
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“while decreasing the expression of those that favor immune-suppressive CD11b+ myeloid cells (e.g., CXCL1-5; CCL9; Chow and Luster, 2014; Kortlever et al., 2017; Liao et al., 2019; Nagarsheth et al., 2017; Fig. 5, I and J).”
From SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling (2021) · cites this paper as Liao et al., 2019
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Lu, W., Yu, W., He, J., Liu, W., Yang, J., Lin, X., Zhang, Y., Wang, X., Jiang, W., Luo, J., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202012798 · Cited by 112
“…Molecular Medicine 13: e12798 | 2021 1 of 20 2 of 20 EMBO Molecular Medicine 13: e12798 | 2021 ª 2020 The Authors Increasing evidence has indicated that immunosuppressive myeloid cells (IMCs) are a prominent driver of immunotherapy resistance in colorectal cancer (Le et al, 2017; Liao et al, 2019).”
BackgroundZhao, D., Cai, L., Lü, X., Liang, X., Li, J., Chen, P., Ittmann, M., Shang, X., Jiang, S., Li, H., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-1352 · Cited by 116
“The poor response of prostate cancer to ICI in the clinic (23) and the key role of MDSCs in suppressing ICI responsiveness in mouse models (28,35,46,47), prompted us to test whether inhibition of the CHD1/IL-6 pathway would improve ICI responsiveness in various mouse models of prostate cancer.”
BackgroundSelf-citationHLA class I loss in colorectal cancer: implications for immune escape and immunotherapy
Anderson, P., Aptsiauri, N., Ruiz-Cabello, F., & Garrido, F. (2021) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00634-7 · Cited by 107
Circadian regulation of cancer cell and tumor microenvironment crosstalk
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Self-citationRoles and mechanisms of tumour-infiltrating B cells in human cancer: a new force in immunotherapy
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“TME-mediated ICI resistance can be induced by cytokines secreted by tumour or stromal cells [6, 7].”
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“This includes expression of GM-CSF and CXCL3 in pancreatic cancer and colon carcinoma, respectively (Pylayeva-Gupta et al. 2012; Liao et al. 2019), as well as CCL9 expression in lung cancer in the context of Myc activation (Kortlever et al. 2017).”
BackgroundCancer cell-intrinsic mechanisms driving acquired immune tolerance
Ghorani, E., Swanton, C., & Quezada, S. A. (2023) · Immunity · doi:10.1016/j.immuni.2023.09.004 · Cited by 116
Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Tang, K. H., Li, S., Khodadadi-Jamayran, A., Jen, J., Han, H., Guidry, K., Chen, T., Hao, Y., Fedele, C., Zebala, J. A., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0369 · Cited by 105
Self-citationOzkan‐Dagliyan, I., Diehl, J. N., George, S. D., Schaefer, A., Papke, B., Klotz‐Noack, K., Waters, A. M., Goodwin, C. M., Gautam, P., Pierobon, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107764 · Cited by 104
“This is consistent with a study of Kras-driven colon cancer, where Kras strongly downregulated IFN-α/γ gene sets, suppressing a T cell immune response (Liao et al., 2019).”
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Convergent inducers and effectors of T cell paralysis in the tumour microenvironment
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Mutant KRAS triggers functional reprogramming of tumor-associated macrophages in colorectal cancer
Liu, H., Liang, Z., Zhou, C., Zeng, Z., Wang, F., Hu, T., He, X., Wu, X., Wu, X., & Lan, P. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00534-2 · Cited by 104
“In addition to the well-identified cell-intrinsic roles of KRAS, there is a growing recognition that KRAS acts via cell-extrinsic mechanisms to favor tumor progression by engaging with the tumor microenvironment.(9,10) As a major component and key orchestrator of the tumor microenvironment, tumor-associated macrophage…”
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The immune microenvironment of colorectal cancer
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Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance
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“Prognostic value of KRAS mutations are controversial [32,33].”
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“A study by DePinho et al. reinforced this therapeutic strategy by showing that inhibition of myeloid-derived suppressor cell recruitment could overcome resistance of tumors expressing KRAS G12D to anti-PD1 therapy 49 .”
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“IRF2 inhibition was found in KRAS-mutated colorectal cancer, contributing to the augmented expression of CXCL3, which binds to CXCR2 on MDSCs to induce migration [25].”
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“reported that oncogenic KRAS represses immune response through the KRAS/interferon regulatory factor 2 axis, resulting in low expression of C- XC motif chemokine ligand 3 and acquired resistance to immunotherapy in colorectal cancer.(47) Additionally, our results directly demonstrate a suppressive immune microenvironm…”
BackgroundTwo-Faced Roles of Tumor-Associated Neutrophils in Cancer Development and Progression
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Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer
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“Restoring IRF2 expression or inhibiting CXCR2, a CXCL3 receptor, reduces MDSC infiltration and enhances T cell-mediated anti-tumor responses in colorectal cancer [133].”
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Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients
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“Mutant KRAS inhibits the expression of interferon regulatory factor 2 (IRF2), a key transcription factor required for the activation of IFN-mediated responses [15].”
BackgroundInfluential
Metadata
- Authors
- Liao, W., Overman, M. J., Boutin, A. T., Shang, X., Zhao, D., Dey, P., Li, J., Wang, G., Lan, Z., Li, J., Tang, M., Jiang, S., Ma, X., Chen, P., Katkhuda, R., Korphaisarn, K., Chakravarti, D., Chang, A., Spring, D. J., Chang, Q., Zhang, J., Maru, D. M., Maeda, D. Y., Zebala, J. A., Kopetz, S., Wang, Y. A., & DePinho, R. A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Syntrix Biosystems (United States) (US)
- Corresponding author
- Wang, Y. Alan
- DePinho, Ronald A.
- ORCID
- Liao, Wenting
- Overman, Michael J.
- Shang, Xiaoying
- Zhao, Di
- Dey, Prasenjit
- Li, Jiexi
- Wang, Guocan
- Li, Jun
- Tang, Ming
- Jiang, Shan
- Ma, Xingdi
- Chen, Peiwen
- Korphaisarn, Krittiya
- Chakravarti, Deepavali
- Chang, Andrew
- Spring, Denise J.
- Chang, Qing
- Zhang, Jianhua
- Maru, Dipen M.
- Maeda, Dean Y.
- Zebala, John A.
- Kopetz, Scott
- Wang, Y. Alan
- DePinho, Ronald A.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 35
- Issue
- 4
- Pages
- 559-572.e7
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC6467776
- OpenAlex
- W2923548794
- Cited by
- 617
- References
- 63
- Citations by year
- 2026: 68 · 2025: 91 · 2024: 104 · 2023: 89 · 2022: 97 · 2021: 86 · 2020: 62 · 2019: 20
- FWCI
- 27.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01 CA084628, PO1 CA117969)
- MD Anderson Colorectal Cancer Moon Shot funds
- National Basic Research Program of China (2015CB554002)
- National Natural Science Foundation of China (81672886, 81773101, 81872401)
- CPRIT (RP170067)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- KRAS G12D, IRF2, CXCL3, CXCR2, colorectal cancer, immune checkpoint inhibitor resistance, anti-PD-1 therapy, myeloid-derived suppressor cells, tumor microenvironment, immunosuppression, transcriptional repression, patient selection
- MeSH terms
- Myeloid-Derived Suppressor Cells, Antineoplastic Agents, Immunological, Adult, Aged, Animals, Cell Movement, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Colorectal Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Drug Resistance, Neoplasm, Tumor Escape, Chemokines, CXC, Receptors, Interleukin-8B, Adenomatous Polyposis Coli Protein, Cell Line, Tumor, Interferon Regulatory Factor-2, Young Adult, Tumor Microenvironment, Programmed Cell Death 1 Receptor
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