Sphingomyelin synthase 2 is a positive regulator of the CSF1R-STAT3 pathway in pancreatic cancer-associated macrophage

Shuhua He; Xiang Gu; Jintong Yang; Fei Xu; Jiachun Hu; Wei Wang; Yiheng Huang; Bin Lou; Tingbo Ding; Lu Zhou; Deyong Ye; Ker Yu; Jibin Dong

doi:10.3389/fphar.2022.902016

Sphingomyelin synthase 2 is a positive regulator of the CSF1R-STAT3 pathway in pancreatic cancer-associated macrophage

Front Pharmacol. 2022 Oct 17:13:902016. doi: 10.3389/fphar.2022.902016. eCollection 2022.

Authors

Shuhua He¹, Xiang Gu¹, Jintong Yang², Fei Xu¹, Jiachun Hu¹, Wei Wang², Yiheng Huang³, Bin Lou¹, Tingbo Ding⁴, Lu Zhou², Deyong Ye², Ker Yu¹, Jibin Dong^{1

5}

Affiliations

¹ Department of Pharmacology and Biochemistry, School of Pharmacy, Fudan University, Shanghai, China.
² Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China.
³ Department of Clinical Medicine, Shanghai Jiaotong University of Medicine, Shanghai, China.
⁴ Experiment & Teaching Center, School of Pharmacy, Fudan University, Shanghai, China.
⁵ Shanghai Engineering Research Center of Immunotherapeutics, Fudan University, Shanghai, China.

Abstract

Background: Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in the pancreatic cancer stroma and are related to the poor prognosis of pancreatic ductal adenocarcinoma (PDAC) patients. Therefore, targeting tumor-associated macrophages is a possible strategy for the treatment of pancreatic cancer. Purpose: We would like to investigate the role of sphingomyelin synthase 2 (SMS2) and the effect of the synthase 2 selective inhibitor YE2 in TAMs and the pancreatic tumor microenvironment. In addition, we also would like to investigate the mechanism by which YE2 attenuates macrophage M2 polarization. Methods: YE2 was utilized to treat macrophages (in vitro) and mice (in vivo). Western blotting and real-time PCR were used to detect the protein levels and mRNA levels of macrophage M2 polarization markers and their downstream signaling pathways. Sphingomyelin synthase 2 gene knockout (KO) mice and their controls were used to establish a PANC-02 orthotopic pancreatic cancer model, and immune cell infiltration in the tumor tissue was analyzed by immunohistochemistry (IHC). Results: We found that sphingomyelin synthase 2 mRNA expression is positively correlated with tumor-associated macrophages, the immunosuppressive microenvironment, and poor prognosis in pancreatic ductal adenocarcinoma patients. Sphingomyelin synthase 2 deficiency was confirmed to have an inhibitory effect on the growth of orthotopic PANC-02 tumors in vivo. The deficiency not only reduced the infiltration of tumor-associated macrophages but also regulated other immune components in the tumor microenvironment. In tissue culture, YE2 inhibited M2 polarization in both bone marrow-derived macrophages (BMDMs) and THP-1 macrophages and eliminated the protumor effect of M2 macrophages. In the mouse model, YE2 treatment reduced the infiltration of TAMs and regulated other immune components in the tumor microenvironment, slowing the progression of PANC-02 tumors. In terms of mechanism, we found that the inhibition of sphingomyelin synthase 2 could downregulate the expression of IL4Rα and CSF1R, thereby attenuating M2 polarization. Conclusion: The sphingomyelin synthase 2 inhibitor YE2 or sphingomyelin synthase 2 deficiency can prevent macrophage M2 polarization in pancreatic cancer, and sphingomyelin synthase 2 could be a new potential target for the treatment of pancreatic cancer.

Keywords: M2-like macrophages; pancreatic ductal adenocarcinoma; sphingomyelin synthase 2; sphingomyelin synthase 2 inhibitor YE2; tumor microenvironment.