title: Interleukin 33 in tumor microenvironment is crucial for the accumulation and function of myeloid-derived suppressor cells.
abstract: Tumor-induced, myeloid-derived suppressor cells (MDSCs)-mediated immune dysfunction is an important mechanism that leads to tumor immune escape and the inefficacy of cancer immunotherapy. Importantly, tumor-infiltrating MDSCs have much stronger ability compared to MDSCs in the periphery. However, the mechanisms that tumor microenvironment induces the accumulation and function of MDSCs are poorly understood. Here, we report that Interleukin-33 (IL-33) - a cytokine which can be abundantly released in tumor tissues both in 4T1-bearing mice and breast cancer patients, is crucial for facilitating the expansion of MDSCs. IL-33 in tumor microenvironment reduces the apoptosis and sustains the survival of MDSCs through induction of autocrine secretion of GM-CSF, which forms a positive amplifying loop for MDSC accumulation. This is in conjunction with IL-33-driven induction of arginase-1 expression and activation of NF-κB and MAPK signaling in MDSCs which augments their immunosuppressive ability, and histone modifications were involved in IL-33 signaling in MDSCs. In ST2-/-mice, the defect of IL-33 signaling in MDSCs attenuates the immunosuppressive and pro-tumoral capacity of MDSCs. Our results identify IL-33 as a critical 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.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Wan
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Bijun
authors.initials: B
authors.lastname: Cui
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Chenyang
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Jiabing
authors.initials: J
authors.lastname: Rong
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Yinjing
authors.initials: Y
authors.lastname: Song
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Luoquan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Jia
authors.initials: J
authors.lastname: He
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Qinchun
authors.initials: Q
authors.lastname: Tan
authors.affiliation: Zhejiang Cancer Hospital , Hangzhou, China.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Wang
authors.affiliation: Zhejiang Cancer Hospital , Hangzhou, China.
authors.forename: Xiying
authors.initials: X
authors.lastname: Shao
authors.affiliation: The affiliated hospital of Hangzhou Normal University , Hangzhou, China.
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine , Hangzhou, China.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
keywords: Autocrine GM-CSF; interleukin 33; myeloid-derived suppressor cells; tumor microenvironment