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

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.

Myeloid cell-expressed MNDA enhances M2 polarization to facilitate the metastasis of hepatocellular carcinoma

“…The transcriptome data showed that 606 genes (329 downregulated and 277 upregulated) were differentially expressed with statistical significance (Figure 4 D and Supplementary Table 3 ). Heatmap showed the significantly downregulation of TGFB1 32 , ETV1 33 , CSF1 34 , BMP7 35 , SGMS2 36 , CXCL14 37 and S100A4 38 which have been reported to enhance protumor macrophage polarization via various pathways. (Figure 4 E).…”

Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: implications for innovative immunotherapy strategies

“…Inhibiting the enzyme with YE2 reduces CSF1R levels and controls macrophage differentiation into the M2 phenotype. Deletions of sphingomyelin synthase 2 or utilization of YE2 can inhibit tumor progression by weakening the invasion and function of TAMs, which may be a promising-targeted treatment scheme ( 177 ).…”

“…MARCO reduces the infiltration of CD8 + T cells and NK cells in PDAC and inhibits effective anti-tumor immunity. The utilization of MARCO-targeted antibodies induces the repolarization of TAMs, improves the level of IL-18, and strengthens the function of anti-tumor cells (176).…”

Myeloid cell-expressed MNDA enhances M2 polarization to facilitate the metastasis of hepatocellular carcinoma

“…4B and supplementary Table 3). Heatmap showed the signi cantly downregulation of CCL22 [32], TGFB1 [33], ETV1 [34], CSF1 [35], BMP7 [36], SGMS2 [37], CXCL14 [38] and S100A4 [39] which have been reported to enhance protumor macrophage polarization via various pathways. (Fig.…”