CD40 controls CXCR5-induced recruitment of myeloid-derived suppressor cells to gastric cancer
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Yixin Ding1,*, Jin Shen1,*, Guangbo Zhang2, Xiaojuan Chen1, JiaMing Wu1, Weichang Chen1,2
1Departments of Gastroenterology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
2Key Laboratory of Medicine and Clinical Immunology of Jiangsu Province, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
*These authors have contributed equally to this work
Weichang Chen, e-mail: [email protected]
Keywords: myeloid-derived suppressor cells, CD40, CXCR5, gastric cancer, immune evasion
Received: June 02, 2015 Accepted: September 29, 2015 Published: October 09, 2015
To explore the mechanisms of MDSC trafficking and accumulation during tumor progression. In this study, we report significant CD40 upregulation in tumor-infiltrating MDSC when compared with splenic MDSC. Microarray analyses comparing CD40high and CD40low MDSC revealed 1872 differentially expressed genes, including CD83, CXCR5, BTLA, CXCL9, TLR1, FLT3, NOD2 and CXCL10. In vivo experiments comparing wild-type (WT) and CD40 knockout (KO) mice demonstrated that CD40 critically regulates CXCR5 expression. Consistently, the transwell analysis confirmed the essential role of CXCR5-CXCL13 crosstalk in the migration of CD40+ MDSC toward gastric cancer. Furthermore, more MDSC accumulated in the gastric cancers of WT mice when compared with KO mice, and the WT tumors mostly contained CD40+ cells. Functionally, tumors grew faster in WT than KO mice. In conclusion, we demonstrate that CD40 expression upregulates the chemokine receptor CXCR5 and promotes MDSC migration toward and accumulation within cancer. Therefore, this study provides preliminary evidence that CD40 may stimulate tumor growth by enabling immune evasion via MDSC recruitment and inhibition of T cell expansion.
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