Department of Neurosurgery, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, China.
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Oncogene. 2022 May;41(22):3131-3150. doi: 10.1038/s41388-022-02324-8. Epub 2022 Apr 29.
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.
慢性炎症性肠病（IBD）与结肠炎相关的肿瘤发生（CAT）的发展密切相关。尽管最近在理解癌症中多形核髓系来源的抑制性细胞（PMN-MDSC）反应方面取得了进展，但这些细胞在这一过程中的机制在很大程度上仍未被描述。在这里，我们发现一种糖蛋白，嗅觉素-4（OLFM4），在结肠炎到结直肠癌（CRC）的PMN-MDSC 中高度表达，其表达水平和 PMN-MDSC 群体与 IBD 向 CRC 的进展呈正相关。此外，骨髓细胞中缺乏 OLFM4 的小鼠表现出PMN-MDSC 募集不良、肠道稳态受损、从 IBD 向 CRC 发展延迟以及对抗 PD1 治疗的反应增强。OLFM4 介导的 PMN-MDSC 活性的主要机制涉及 NF-κB/PTGS2 途径，通过结合 LGALS3，一种在 PMN-MDSC 上表达的半乳糖结合蛋白。我们的结果表明，OLFM4/NF-κB/PTGS2 途径促进了 PMN-MDSC 的募集，这在维持肠道稳态中起着至关重要的作用，但在 CRC 中对抗 PD1 治疗表现出耐药性。
