PO.IM02.02 · 免疫学
早期肝细胞癌发生过程中ILC和ILTC反应的动力学分析揭示IL-15-ILC1轴
Kinetic profiling of ILC and ILTC responses during early hepatocellular carcinoma development reveals IL-15-ILC1 axis
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
癌症免疫治疗主要聚焦于常规T细胞，因为它们能识别精确的肽抗原。然而，尽管近期取得突破，包括将免疫检查点抑制剂治疗作为不可切除肝细胞癌（HCC）的一线治疗，但HCC相关的总体死亡率仍在上升。固有淋巴细胞（ILC）和固有样T细胞（ILTC）是在炎症、组织修复和免疫耐受中发挥关键作用的淋巴细胞群体。我们此前利用单细胞RNA测序和流式细胞术对已确诊HCC患者的肿瘤样本进行研究，证明肿瘤细胞因子环境控制ILC组成和HCC结局（Heinrich等，Gut 2022）。然而，它们在肿瘤发生和进展过程中的动态作用，尤其在肿瘤起始的早期阶段，仍知之甚少。我们决定在小鼠HCC模型中研究ILC和ILTC，这使我们能够在极早期肿瘤发生过程中进行时间分析和功能研究。利用高维流式细胞术、单细胞RNA测序和组织学成像相结合，我们在质粒诱导（MYC-Luc;sg-p53）的HCC小鼠模型中表征了这些群体的时间性变化。大多数ILC和ILTC群体，包括黏膜相关恒定T（MAIT）细胞、1组ILC、ILC2和ILC3，在第4天时扩增，但随着肿瘤进展失去了细胞毒性颗粒的产生。我们确定肝脏驻留的表达Hobit的ILC1为抗肿瘤免疫的关键效应细胞，因为它们的缺失导致早期肿瘤负荷显著增加。单细胞RNA测序显示1组ILC出现显著的表型多样化，最终随肿瘤进展转向耗竭状态。此外，细胞因子和转录数据提示早期肿瘤来源的IL-15是肝脏ILC1的早期介导者和激活剂。总之，我们的发现将ILC和ILTC定位为对致癌转化的快速反应者，其中ILC1作为早期抗肿瘤防御的关键介导者发挥作用。
查看英文原文 English abstract
Cancer immunotherapy has largely focused on conventional T cells due to their recognition of precise peptide-antigens. However, despite recent breakthroughs, including the adoption of immune checkpoint inhibitor therapy as first-line therapy for unresectable hepatocellular carcinoma (HCC), the overall mortality associated with HCC continues to rise. Innate lymphoid cells (ILC) and innate-like T cells (ILTC) are lymphoid populations that play critical roles in inflammation, tissue repair, and immune tolerance. Using single cell RNA sequencing and flow cytometry on tumor samples from patients with established HCC, we have previously shown that the tumor cytokine milieu controls ILC composition and HCC outcome (Heinrich et al. Gut 2022). However, their dynamic roles during tumor development and progression particularly in the early phases of tumor initiation are poorly understood. We decided to study ILCs and ILTCs in murine HCC models, which allows us to perform temporal analysis and functional studies during very early tumor development. Using a combination of high-dimensional flow cytometry, single-cell RNA sequencing, and histologic imaging, we characterized the temporal shifts in these populations in a plasmid-induced (MYC-Luc;sg-p53) HCC mouse model. Most ILC and ILTC populations including mucosal-associated invariant T (MAIT) cells, group 1 ILCs, ILC2s, and ILC3s expanded by day 4, but lost cytotoxic granule production as the tumors progressed. We identified liver resident Hobit-expressing ILC1s as pivotal effectors of anti-tumor immunity, as their loss led to a significant increase in early tumor burden. Single-cell RNA sequencing demonstrated substantial phenotypic diversification in group 1 ILCs which ultimately shift towards an exhausted state as tumors progressed. Additionally, cytokine and transcriptional data suggested early tumor-derived IL-15 to be an early mediator and activator of hepatic ILC1s. Together, our findings position ILCs and ILTCs as rapid responders to oncogenic transformation, with ILC1s functioning as critical mediators of early anti-tumor defense.
利益披露 Disclosure
P. Huang, None..
R. Trehan, None..
B. Ruf, None..
C. Ma, None..
D. Soika, None..
L. Kocheise, None..
G. B. Prata, None..
T. F. Greten, None..
F. Korangy, None.