OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment
OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment
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DOI：
10.1038/s41388-022-02324-8
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发表时间：
2022-04-29
期刊：
影响因子：
8
通讯作者：
He, Yumei
中科院分区：
文献类型：
--
作者：
Chen, Ziyang;Zhang, Xiaogang;He, Yumei
慢性炎症性肠病(IBD)与结肠炎相关肿瘤发生(CAT)密切相关。尽管最近对肿瘤中多形核髓系衍生抑制细胞(PMN-MDSC)反应的了解取得了进展，但这些细胞在这一过程中的机制在很大程度上仍不清楚。在此，我们发现一种糖蛋白OLFM4在从结肠炎到结直肠癌(CRC)的PMN-MDSC中高表达，其表达水平和PMN-MDSC数量与IBD向CRC的发展呈正相关。此外，在髓系细胞中缺乏OLFM4的小鼠表现出PMN-MDSCs募集不良，肠道内环境平衡受损，从IBD到CRC的发育延迟，以及对抗PD1治疗的反应性增强。OLFM4介导的PMN-MDSC活性的主要机制是通过与表达在PMN-MDSC上的半乳糖苷结合蛋白LGALS3的结合，通过NF-kappa B/Ptgs2途径发挥作用。我们的结果表明，OLFM4/NF-kappa B/Ptgs2通路促进了PMN-MDSC的募集，在维持肠道内环境稳定方面发挥了重要作用，但对抗PD1治疗表现出抵抗。
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-kappa B/PTGS2 pathway, through the binding of LGALS3, a galactoside-binding protein expressed on PMN-MDSCs. Our results showed that the OLFM4/NF-kappa B/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.