TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host

Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous cells derived from the bone marrow and they are the major component of the tumor-induced immunosuppressive environment. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, catalyzes the polyubiquitination of target proteins. TRAF6 plays a critical role in modulating the immune system. However, whether TRAF6 is involved in the regulation of MDSCs has not been thoroughly elucidated to date. In this study, we found that the expression of TRAF6 in MDSCs derived from tumor tissue was significantly upregulated compared with that of MDSCs from spleen of tumor-bearing mice. Knockdown of TRAF6 remarkably attenuated the immunosuppressive effects of MDSCs. Mechanistically, TRAF6 might improve the immunosuppression of MDSCs by mediating K63-linked polyubiquitination and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Additionally, it was discovered that the accumulation of MDSCs was abnormal in peripheral blood of lung cancer patients. TRAF6 and arginase 1 were highly expressed in MDSCs of patients with lung cancer. Taken together, our study demonstrated that TRAF6 participates in promoting the immunosuppressive function of MDSCs and provided a potential target for antitumor immunotherapy.