OLFM4 deficiency delays the progression of colitis to colorectal cancer by abrogating PMN-MDSCs recruitment.

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.

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation.

The endothelin-A receptor antagonist BQ123 is an effective treatment agent for hypertension and obese cardiomyopathy. However, the role of BQ123 in controlling acute inflammatory diseases and its underlying mechanisms are not well understood. Here, we showed that BQ123 activated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in mice and that the IL13/STAT6/Arg1 signaling pathway is involved in this process. Importantly, both treatment with BQ123 and the transfer of BQ123-induced PMN-MDSCs (BQ123-MDSCs) were effective in relieving inflammation, including dextran sulfate sodium (DSS)-induced colitis, papain-induced pneumonia, and concanavalin A (ConA)-induced hepatitis, in mice. The treatment effects were mediated by the attenuation of the inflammation associated with the accumulation of PMN-MDSCs in the colon, lung, and liver. However, concurrent injection of Gr1 agonistic antibody with BQ123 induced PMN-MDSC aggravated the observed acute inflammation. Interestingly, no remission of inflammation was observed in Rag2 knockout mice administered BQ123-MDSCs, but co-injection with CD3+ T cells significantly relieved acute inflammation. In summary, BQ123-induced PMN-MDSCs attenuated acute inflammation in a T cell-dependent manner, providing a novel potential strategy to prevent the occurrence of acute inflammation.