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Prdm1 正向调控肝脏 ILC1 群体的肿瘤免疫监视并维持其功能异质性。

Prdm1 positively regulates liver Group 1 ILCs cancer immune surveillance and preserves functional heterogeneity.

机构信息

Institute of Medical Engineering & Translational Medicine, Tianjin University, Tianjin, China.

Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

出版信息

Elife. 2024 Aug 12;13:RP92948. doi: 10.7554/eLife.92948.

DOI:10.7554/eLife.92948
PMID:39133873
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11318973/
Abstract

Group 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and type 1 innate lymphoid cells (ILC1s). The main functions of liver cNK cells and ILC1s not only include directly killing target cells but also regulating local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of liver cNK cells and ILC1s, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role of in shaping the composition and maturation of cNK cells. Although did not affect the killing function of cNK cells in an in vivo cytotoxicity model, a significant increase in cancer metastasis was observed in knockout mice. Interferon-gamma (IFN-γ), granzyme B, and perforin secretion decreased significantly in -deficient cNK cells and liver ILC1s. Single-cell RNA sequencing (scRNA-seq) data also provided evidences that Prdm1 maintains functional subsets of cNK cells and liver ILC1s and facilitates communications between cNK cells, liver ILC1s, and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in cNK cells and liver ILC1s, showing promising potential for developing innovative immune therapy strategies against liver cancer.

摘要

第一组先天淋巴细胞（ILCs）包括常规自然杀伤（cNK）细胞和 I 型先天淋巴细胞（ILC1）。肝 cNK 细胞和 ILC1 的主要功能不仅包括直接杀伤靶细胞，还通过细胞因子的分泌调节肝局部免疫微环境。揭示转录因子调节和影响肝 cNK 细胞和 ILC1 功能的复杂机制，特别是在肝肿瘤的背景下，为增强针对肝恶性肿瘤的免疫疗法的效果提供了一个重要机会。利用 Ncr1 驱动的条件敲除小鼠模型，我们的研究揭示了在塑造 cNK 细胞组成和成熟中的作用。虽然在体内细胞毒性模型中不影响 cNK 细胞的杀伤功能，但在 敲除小鼠中观察到癌症转移显著增加。IFN-γ、颗粒酶 B 和穿孔素在 -缺陷的 cNK 细胞和肝 ILC1 中的分泌显著减少。单细胞 RNA 测序（scRNA-seq）数据还提供了证据，表明 Prdm1 维持 cNK 细胞和肝 ILC1 的功能亚群，并促进 cNK 细胞、肝 ILC1 和巨噬细胞之间的通讯。本研究揭示了 Prdm1 在 cNK 细胞和肝 ILC1 中的新的调节机制，为开发针对肝癌的创新免疫治疗策略展示了有前途的潜力。

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