Depletion of Gr1+ Myeloid Cells Attenuates High-Fat-diet-aggravated Esophageal Squamous Cell Carcinoma in Mice.

Obesity is a leading cause of multiple cancers, but whether it promotes esophageal squamous cell carcinoma (ESCC) and its underlying cancer-promoting mechanism remains unclear. To evaluate the effect of a high-fat diet (HFD) on ESCC and explore the role and mechanism of myeloid-derived suppressor cells (MDSCs) in HFD-induced ESCC, C57BL/6J mice were treated with 4-nitroquinoline 1-oxide (4NQO) to induce ESCC and randomly assigned to an HFD or a normal-fat diet. An anti-Gr1 monoclonal antibody was used to deplete MDSCs in the context of experimental diets and ESCC induction. The expression of MDSC markers CD11b and Gr1 and immune checkpoints (ICs) PD1, TIM3, and VISTA in lesions were detected by immunohistochemistry. The correlation between myeloid cell markers (CD11b and CD33) and ICs and their relationship with ESCC patient prognosis were further analyzed using the The Cancer Genome Atlas dataset. The results showed that HFD accelerated esophageal carcinogenesis, induced MDSC expansion, and upregulated IC expression, whereas depletion of Gr1+ myeloid cells significantly suppressed tumor growth, decreased the number of MDSCs, and downregulated IC expression in HFD mice. PD1, TIM3, and VISTA expressions were positively correlated with myeloid cell marker expression in human ESCC. Moreover, the high expression of IC molecules was associated with poor survival in patients with ESCC. These data indicate that HFD promotes the initiation and development of ESCC. Gr1+ myeloid cell targeting significantly inhibited ESCC formation in HFD mice, which may be associated with IC downregulation.