NCR− group 3 innate lymphoid cells orchestrate IL-23/IL-17 axis to promote hepatocellular carcinoma developmentResearch in context
Yonghao Liu,
Yuan Song,
Dandan Lin,
Lei Lei,
Yu Mei,
Ziqi Jin,
Huanle Gong,
Ying Zhu,
Bo Hu,
Yinsheng Zhang,
Lixiang Zhao,
Huey Yee Teo,
Ju Qiu,
Wen Jiang,
Chen Dong,
Depei Wu,
Yuhui Huang,
Haiyan Liu
Affiliations
Yonghao Liu
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China; Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China
Yuan Song
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore
Dandan Lin
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Lei Lei
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Yu Mei
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore
Ziqi Jin
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Huanle Gong
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Ying Zhu
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Bo Hu
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Yinsheng Zhang
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Lixiang Zhao
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China
Huey Yee Teo
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore
Ju Qiu
The Key Laboratory of Stem Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
Wen Jiang
Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chen Dong
Institute of Immunology and School of Medicine, Tsinghua University, Beijing 100084, China
Depei Wu
Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215006, China; Correspondence to: D. Wu, Institute of Blood and Marrow Transplantation and Collaborative Innovation Center of Hematology, Soochow University, China and the First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Yuhui Huang
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China; Correspondence to: Y. Huang, Cyrus Tang Hematology Center, State Key Laboratory of Radiation Medicine and Protection, Soochow University, 199 Ren-Ai Road, Suzhou 215123, Jiangsu, China.
Haiyan Liu
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore; Correspondence to: H. Liu, Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore.
Background: Innate lymphoid cells (ILCs) are a newly discovered family of immune cells that have similar cytokine-secreting profiles as T helper cell subsets. Although ILCs are critical for host defense against infections and tissue homeostasis, their roles in tumor development are not well established. Methods: We studied the function of ILC3 cells in the liver for the development of hepatocellular carcinoma (HCC) in murine HCC models using flow cytometry, adoptive transfer, and in vitro functional assays. Findings: We found that ILC3 lacking the natural cytotoxicity-triggering receptor (NCR−ILC3) promoted the development of HCC in response to interleukin 23 (IL-23). IL-23 serum level is elevated in HCC patients and its high expression is associated with poor clinical outcomes. We found that IL-23 could promote tumor development in murine HCC tumor models. IL-23 promoted the expansion of NCR−ILC3 and its differentiation from group 1 ILCs (ILC1s). Furthermore, NCR−ILC3 initiated IL-17 production upon IL-23 stimulation and directly inhibited CD8+ T cell immunity by promoting lymphocyte apoptosis and limiting their proliferation. Interpretation: Together, our findings suggest that NCR−ILC3 initiates the IL-17-rich immunosuppressive tumor microenvironment and promotes the development of HCC, thus may serve as a promising target for future cancer immunotherapy. Fund: This work was supported by grants from National Natural Science Foundation of China (81471586, 81571556), the Priority Academic Program Development of Jiangsu Higher Education Institutions, the collaborative Innovation Center of Hematology, start-up grant from National University of Singapore, the Cancer Prevention and Research Institute of Texas CPRIT (RR180017), and the National Cancer Institute's Cancer Center Support (Core) Grant CA016672 (to The University of Texas MD Anderson Cancer Center). Keywords: IL-23, IL-17, ILC, Tumor microenvironment, HCC
