Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou, China.
Hepatology. 2021 Nov;74(5):2526-2543. doi: 10.1002/hep.31855. Epub 2021 Oct 4.
Due to their inherent characteristics, the function of group-2 innate lymphoid cells (ILC2s) varies in a context-dependent manner. ILC2s are involved in certain liver diseases; however, their involvement in HCC is unknown. In the present study, we assessed the role of an HCC-derived ILC2 population in tumor progression.
Through FACS and single-cell RNA sequencing, we discovered that ILC2s were highly enriched in human HCC and correlated significantly with tumor recurrence and worse progression-free survival as well as overall survival in patients. Mass cytometry identified a subset of HCC-derived ILC2s that had lost the expression of killer cell lectin-like receptor subfamily G, member 1 (KLRG1). Distinct from their circulating counterparts, these hepatic ILC2s highly expressed CD69 and an array of tissue resident-related genes. Furthermore, reduction of E-cadherin in tumor cells caused the loss of KLRG1 expression in ILC2s, leading to their increased proliferation and subsequent accumulation in HCC sites. The KLRG1 ILC2 subset showed elevated production of chemotaxis factors, including C-X-C motif chemokine (C-X-C motif) ligand (CXCL)-2 and CXCL8, which in turn recruited neutrophils to form an immunosuppressive microenvironment, leading to tumor progression. Accordingly, restoring KLRG1 in ILC2s, inhibiting CXCL2 in ILC2s, or depleting neutrophils inhibited tumor progression in a murine HCC model.
We identified HCC-associated ILC2s as an immune regulatory cell type that promotes tumor development, suggesting that targeting these ILC2s might lead to new treatments for HCC.
由于其固有特性，群 2 先天淋巴样细胞（ILC2）的功能以依赖于上下文的方式变化。ILC2 参与某些肝脏疾病；然而，它们在 HCC 中的参与情况尚不清楚。在本研究中，我们评估了 HCC 衍生的 ILC2 群体在肿瘤进展中的作用。
通过 FACS 和单细胞 RNA 测序，我们发现 ILC2 在人 HCC 中高度富集，并与肿瘤复发以及患者无进展生存期和总生存期显著相关。质谱细胞术鉴定出 HCC 衍生的 ILC2 的一个亚群，其丧失了杀伤细胞凝集素样受体亚家族 G，成员 1（KLRG1）的表达。与循环中的对应物不同，这些肝 ILC2 高度表达 CD69 和一系列组织驻留相关基因。此外，肿瘤细胞中 E-钙粘蛋白的减少导致 ILC2 中 KLRG1 的表达丧失，导致其增殖增加，并随后在 HCC 部位积累。KLRG1 ILC2 亚群表现出趋化因子（包括 C-X-C 基序趋化因子（C-X-C 基序）配体（CXCL）-2 和 CXCL8）的产生增加，这反过来又招募中性粒细胞形成免疫抑制微环境，导致肿瘤进展。因此，在小鼠 HCC 模型中，恢复 ILC2 中的 KLRG1、抑制 ILC2 中的 CXCL2 或耗尽中性粒细胞可抑制肿瘤进展。
我们鉴定出与 HCC 相关的 ILC2 作为促进肿瘤发展的免疫调节细胞类型，表明靶向这些 ILC2 可能为 HCC 提供新的治疗方法。
