title: Epstein-Barr virus-induced gene 3-deficiency leads to impaired antitumor T-cell responses and accelerated tumor growth.
abstract: Epstein-Barr virus-induced gene 3 (EBI3) encoded protein can form heterodimers with IL-27P28, and IL-12P35 to form IL-27, and IL-35. However, IL-27 stimulates, whereas IL-35 inhibits antitumor T-cell responses. IL-27 also limits the Foxp3+regulatory T cell (Treg) population, whereas IL-35 has been shown to expand Tregs and foster Treg suppressive functions. It remains unclear which group of forces are dominant during antitumor T-cell responses. In this study, we evaluated the tumor growth and antitumor T-cell responses in EBI3-deficient mice that lack both IL-27 and IL-35. We found that injecting B16 melanoma cells into EBI3-deficient C57BL/6 mice, or J558 plasmacytoma cells into EBI3-deficient BALB/c mice resulted in significantly increased tumor growth relative to those implanted in wild-type control mice. Tumors from EBI3-deficient mice contained significantly decreased proportions of CD8+T cells and increased proportions of CD4+FoxP3+Treg cells as compared to those from EBI3-intact mice. Tumor-infiltrating T cells from EBI3-deficient mice were impaired in their capacity to produce IFNγ. Phenotypically, Tregs from EBI3-deficient mice were highly suppressive and produced IL-10 in the tumor microenvironment. Depletion of Tregs or inactivation of the IL-10 pathway significantly abrogated tumor growth enhancement inEbi3-/-mice. Finally, we showed thatEbi3-/-mice administered a melanoma vaccine failed to mount a CD8+T-cell response and the vaccine failed to confer tumor rejection in EBI3-deficient mice. Taken together, these results suggest thatEbi3-/-mice show a phenotype of IL-27-deficiency rather than IL-35-deficiency during anti-tumor T-cell responses. Thus, our results suggest that endogenous IL-27 is critical for both spontaneous and vaccine-induced antitumor T-cell responses.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA.
authors.forename: Jin-Qing
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA ; Department of Gastroenterology; Guangdong Provincial Key Laboratory of Gastroenterology; Nanfang Hospital; Southern Medical University ; Guangzhou, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA ; Department of Gastroenterology; Guangdong Provincial Key Laboratory of Gastroenterology; Nanfang Hospital; Southern Medical University ; Guangzhou, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA ; Department of Hepatobiliary Surgery; Nanfang Hospital; Southern Medical University ; Guangzhou, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Gastroenterology; Guangdong Provincial Key Laboratory of Gastroenterology; Nanfang Hospital; Southern Medical University ; Guangzhou, China.
authors.forename: Ming-Song
authors.initials: MS
authors.lastname: Li
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Davis Medical Center; Department of Molecular and Cellular Biochemistry; Ohio State University ; Columbus, OH USA.
authors.forename: Lai-Chu
authors.initials: LC
authors.lastname: Wu
authors.affiliation: Cancer Immunology; Inflammation, and Tolerance Program; Georgia Regents University Cancer Center ; Augusta, GA USA.
authors.forename: Yukai
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Thoracic Surgery; Xinqiao Hospital; Third Military Medical University ; Chongqing, China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Comprehensive Cancer Center; Ohio State University ; Columbus, OH USA.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Bai
keywords: APC, antigen-presenting cells; CTL, cytotoxic T lymphocyte; EBI3, Epstein-Barr virus-induced gene 3; Th, T helper; Treg, regulatory T cells.; Epstein-Barr virus-induced gene 3; IL-27; IL-35; Treg; tumor immunity