title: Overrepresentation of IL-10-Expressing B Cells Suppresses Cytotoxic CD4+ T Cell Activity in HBV-Induced Hepatocellular Carcinoma.
abstract: Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis and low five-year survival rate. A strong and effective CD4+ T cell-mediated cytotoxicity was associated with better survival and low recurrence rate in HCC, but the regulatory mechanism that controls CD4+ T cell cytotoxicity in HCC patients is not fully examined. Given that IL-10-expressing B cells could suppress the inflammation of cytotoxic CD8+ T cells, T helper 1 (Th1) cells and Th17 cells, while promoting regulatory T (Treg) cell differentiation, we examined the role of IL-10-expressing B cells in HBV-related HCC patients. We found that compared to healthy controls, HCC patients exhibited significantly higher frequencies of IL-10-expressing B cells, which were negatively correlated with the frequencies of granzyme A, granzyme B, and perforin expressing CD4+ T cells. Surface molecule Tim-1 was preferentially expressed on IL-10-expressing B cells. Therefore, we separated total B cells into Tim-1+ and Tim-1- B cells. CD4+ T cells incubated with Tim-1+ B cells exhibited significantly reduced levels of granzyme A, granzyme B and perforin expression, compared to the CD4+ T cells incubated with Tim-1- B cells. Antagonizing IL-10 in culture rescued CD4+ T cell cytotoxicity. Compared to that in peripheral blood, the level of IL-10-expressing B cells were further upregulated in resected tumor, while the level of CD4+ cytotoxic T cells was downregulated. The negative correlations between IL-10-expressing B cells and CD4+ cytotoxic T cells were also observed in tumor-infiltrating cells. Together, our data revealed an additional antitumor mechanism mediated by IL-10-expressing B cells.
authors.affiliation: Department of Oncology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Xue
authors.affiliation: Department of Interventional Radiology, Hainan Province People's Hospital, Haikou, Hainan, 570311, China.
authors.forename: Fuhuang
authors.initials: F
authors.lastname: Lin
authors.affiliation: Department of Hepatobiliary Surgery, Linyi People's Hospital, Shandong, 276000, China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Tan
authors.affiliation: Department of Medicine, Sixth People''s Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zun-Qiang
authors.initials: ZQ
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Sixth People''s Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Zhang-Yun
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, Linyi People's Hospital, Shandong, 276000, China.
authors.forename: Ludong
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000378:metabolism; D006515:Hepatitis B virus / Q000472:pathogenicity*; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D054353:Perforin / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism
chemical_list: C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; C508609:IL10 protein, human; D054353:Perforin; D016753:Interleukin-10; D053804:Granzymes