The Role Of Interleukin-33 In Regulating The Accumulation And Function Of Myeloid-derived Suppressor Cells In Tumor Microenvironment

Tumor-infiltrating immune regulatory cells are main participants responsible for the down-regulated antitumor immunity and tumor immune escape as well as the inefficacy of cancer immunotherapy. Among these cells, myeloid-derived suppressor cells (MDSCs) are found in various kinds of tumors and can infiltrate into tumor mass where they inhibit antitumor immune response. However, the mechanisms that tumor microenvironment regulates the accumulation and function of MDSCs are poorly understood.Herein, we reported that as a DAMP molecule, interleukin-33 (IL-33) is highly expressed and released within breast tumors both in mice an human, compared with low IL-33 levels in serum. We also found that tumor-infiltrating MDSCs expressed ST2-the receptor subunit for IL-33, suggesting that MDSC might be the target cells regulated by IL-33 in tumor microenvironment.Next we compared MDSC frenquencies between tumor-bearing ST2 KO and WT mice, and found that the deficiency of IL-33/ST2 signaling significantly decreased the accumulation of MDSCs within tumor microenvironment. Further results showed that IL-33 in tumor microenvironment reduced the apoptosis and sustained the survival of MDSCs through induction of autocrine secretion of GM-CSF in MDSCs, which forms a positive amplifying loop for MDSC accumulation. On the other hand, IL-33 augments the suppressive ability of MDSCs to inhibit T-cell proliferation by increasing the expression and enzymatic activity of arginase-1.It is noteworthy that IL-33 mainly regulates the accumulation and function of tumor-infiltrating MDSCs rather than peripheral MDSCs, by reason that IL-33 are highly produced only within tumor tissues. These results can help to explain the way that microenvironment influence the function of MDSCs.Furthermore, we performed adoptive-transfer experiments and found that the deficiency of IL-33/ST2 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral effects of MDSCs. At last we revealed that NF-κB and ERK were crucial transcription factors for IL-33 signaling in MDSCs. In summary, our results identify IL-33 as a novel mediator that contributes to the abnormal expansion and enhanced immunosuppressive function of MDSCs within tumor microenvironment, which can be potentially targeted to reverse MDSC-mediated tumor immune evasion.