OLFM4 Deficiency Delays the Progression of Colitis to Colorectal Cancer by Abrogating PMN-MDSCs Recruitment
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Chronic inflammatory bowel disease (IBD) is strongly associated with the development of colitis-associated tumorigenesis (CAT). Despite recent advances in the understanding of polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) responses in cancer, the mechanisms of these cells during this process remain largely uncharacterized. Here, we discovered a glycoprotein, olfactomedin-4 (OLFM4), was highly expressed in PMN-MDSCs from colitis to colorectal cancer (CRC), and its expression level and PMN-MDSC population positively correlated with the progression of IBD to CRC. Moreover, mice lacking OLFM4 in myeloid cells showed poor recruitment of PMN-MDSCs, impaired intestinal homeostasis, and delayed development from IBD to CRC, and increased response to anti-PD1 therapy. The main mechanism of OLFM4-mediated PMN-MDSC activity involved the NF-κB/PTGS2 pathway, through the binding of LGALS3, a galactoside-binding protein expressed on PMN-MDSCs. Our results showed that the OLFM4/NF-κB/PTGS2 pathway promoted PMN-MDSC recruitment, which played an essential role in the maintenance of intestinal homeostasis, but showed resistance to anti-PD1 therapy in CRC.
Li C, Xue Y, Yinwang E, Ye Z Cancer Rep (Hoboken). 2025; 8(2):e70044.
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Chen X, Zhou B, Wang S, Jiang X, Ping Y, Xia J Cancer Cell Int. 2024; 24(1):399.
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OLFM4 modulates intestinal inflammation by promoting IL-22ILC3 in the gut.
Xing Z, Li X, He J, Chen Y, Zhu L, Zhang X Commun Biol. 2024; 7(1):914.
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Li S, Long X MedComm (2020). 2024; 5(7):e602.
PMID: 38911064 PMC: 11193132. DOI: 10.1002/mco2.602.
Role played by MDSC in colitis-associated colorectal cancer and potential therapeutic strategies.
Wang K, Wang Y, Yin K J Cancer Res Clin Oncol. 2024; 150(5):243.
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