title: Polarization of Tissue-Resident TFH-Like Cells in Human Hepatoma Bridges Innate Monocyte Inflammation and M2b Macrophage Polarization.
abstract: The existence, regulation, and functions of IL21+immune cells are poorly defined in human cancers. Here, we identified a subset of protumorigenic IL21+TFH-like cells in human hepatocellular carcinoma. These cells were the major source of IL21 in tumors and represented about 10% of the CD4+T-cell population at levels comparable with the TFHcells present in lymph nodes. However, these TFH-like cells displayed a unique CXCR5-PD-1lo/-BTLA-CD69hitissue-resident phenotype with substantial IFNγ production, which differed from the phenotype of TFHcells. Toll-like receptor 4 (TLR4)-elicited innate monocyte inflammation was important for IL21+TFH-like cell induction in tumors, and activation of STAT1 and STAT3 was critical for TFH-like cell polarization in this process. Importantly, the TFH-like cells operated in IL21-IFNγ-dependent pathways to induce plasma cell differentiation and thereby create conditions for protumorigenic M2b macrophage polarization and cancer progression. Thus, induction of TFH-like cells links innate inflammation to immune privilege in tumors.
  
  
  
  We identified a novel protumorigenic IL21+TFH-like cell subset with a CXCR5-PD-1-BTLA-CD69hitissue-resident phenotype in hepatoma. TLR4-mediated monocyte inflammation and subsequent T-cell STAT1 and STAT3 activation are critical for TFH-like cell induction. TFH-like cells operate via IL21-IFNγ pathways to induce plasma cells and create conditions for M2b macrophage polarization. Cancer Discov; 6(10); 1182-95. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 1069.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China. State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Min-Min
authors.initials: MM
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Xiang-Ming
authors.initials: XM
authors.lastname: Lao
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Rui-Xian
authors.initials: RX
authors.lastname: Liu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qiu-Hui
authors.initials: QH
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: Jun-Cheng
authors.initials: JC
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Fang-Zhu
authors.initials: FZ
authors.lastname: Ouyang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Dong-Ping
authors.initials: DP
authors.lastname: Chen
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ka-Wo
authors.initials: KW
authors.lastname: Chan
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Dai-Chao
authors.initials: DC
authors.lastname: Shi
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. kdming@mail.sysu.edu.cn.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Kuang
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D006528:Carcinoma, Hepatocellular / Q000276:immunology*; D002454:Cell Differentiation; D016764:Cell Polarity; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008113:Liver Neoplasms; D008264:Macrophages / Q000502:physiology*; D009000:Monocytes / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C573415:IFNG protein, human; D007378:Interleukins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma; D000098546:Interleukin-21