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.
Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, National University of Singapore, Singapore 117456, Singapore.
EBioMedicine. 2019 Mar;41:333-344. doi: 10.1016/j.ebiom.2019.02.050. Epub 2019 Mar 1.
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.
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.
We found that ILC3 lacking the natural cytotoxicity-triggering receptor (NCRILC3) 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 NCRILC3 and its differentiation from group 1 ILCs (ILC1s). Furthermore, NCRILC3 initiated IL-17 production upon IL-23 stimulation and directly inhibited CD8 T cell immunity by promoting lymphocyte apoptosis and limiting their proliferation.
Together, our findings suggest that NCRILC3 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).
先天淋巴细胞（ILCs）是一类新发现的免疫细胞家族，其细胞因子分泌谱与辅助性 T 细胞亚群相似。尽管 ILCs 对于宿主抗感染和组织稳态至关重要，但它们在肿瘤发展中的作用尚未得到充分证实。
我们使用流式细胞术、过继转移和体外功能测定研究了 ILC3 在肝脏中的功能，以研究其在小鼠肝癌（HCC）模型中发生的作用。
我们发现缺乏自然细胞毒性触发受体（NCRILC3）的 ILC3 可促进白细胞介素 23（IL-23）应答引起的 HCC 发展。HCC 患者的血清 IL-23 水平升高，其高表达与不良的临床结局相关。我们发现 IL-23 可促进小鼠 HCC 肿瘤模型中的肿瘤发展。IL-23 促进了 NCRILC3 的扩增及其从 ILC1 分化而来。此外，NCRILC3 在受到 IL-23 刺激后启动了 IL-17 的产生，并通过促进淋巴细胞凋亡和限制其增殖来直接抑制 CD8 T 细胞免疫。
总之，我们的研究结果表明，NCRILC3 启动了富含 IL-17 的免疫抑制性肿瘤微环境，并促进了 HCC 的发展，因此可能成为未来癌症免疫治疗的一个有希望的靶点。
本工作得到了国家自然科学基金（81471586、81571556）、江苏省高校优势学科建设工程、血液学协同创新中心、新加坡国立大学启动资金、德克萨斯州癌症预防与研究所 CPRIT（RR180017）以及美国国立癌症研究所癌症中心支持（核心）拨款 CA016672（德克萨斯大学 MD 安德森癌症中心）的资助。
