The DOI matches its Crossref record; 62 of the 63 references it cites were found in a registry or an index.
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]
In the citing paper
“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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“For example, oncogenic signaling K-Ras regulates the expression of CXCL3, a key chemokine for myeloid cell recruitment (Liao et al., 2019).”
BackgroundInflammation and tumor progression: signaling pathways and targeted intervention
Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y., & Li, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00658-5 · Cited by 3,058
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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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