北京大学张宁等研究人员合作揭示肝脏肿瘤的免疫微环境亚型和中性粒细胞的异质性。相关论文于2022年11月9日在线发表于国际学术期刊《自然》。

研究人员对收集自124名肝癌患者和8只小鼠的189个样本进行了单细胞RNA测序（scRNA-seq）分析。通过分析100多万个细胞，研究人员将患者分为五个肿瘤免疫微环境（TIME）亚型，包括免疫激活、由髓系细胞或基质细胞介导的免疫抑制、免疫排斥和免疫驻留表型。不同的TIME亚型在空间上是有组织的，与趋化因子网络和基因组特征有关。

值得注意的是，肿瘤相关的中性粒细胞（TAN）群体富集在髓系细胞富集的亚型中，与不利的预后有关。通过体外诱导TAN和对患者TAN的体外分析，研究人员显示CCL4⁺ TAN可以招募巨噬细胞，PD-L1⁺ TAN可以抑制T细胞的细胞毒性。此外，对小鼠中性粒细胞亚群的scRNA-seq分析显示，它们与人类的中性粒细胞亚群基本一致。在小鼠模型中，体内中性粒细胞的耗竭削弱了肿瘤的发展，从而证实了TAN的促肿瘤表型。通过这种详细的肝癌细胞异质性景观，这项研究说明了不同的TIME亚型，突出了TAN的免疫抑制功能，并揭示了靶向TAN的潜在免疫疗法。

据介绍，由各种免疫和基质细胞组织的TIME的异质性是导致肿瘤转移、复发和耐药性的主要因素，但不同的TIME亚型与肝癌的临床相关性如何仍不清楚。

附：英文原文

Title: Liver tumour immune microenvironment subtypes and neutrophil heterogeneity

Author: Xue, Ruidong, Zhang, Qiming, Cao, Qi, Kong, Ruirui, Xiang, Xiao, Liu, Hengkang, Feng, Mei, Wang, Fangyanni, Cheng, Jinghui, Li, Zhao, Zhan, Qimin, Deng, Mi, Zhu, Jiye, Zhang, Zemin, Zhang, Ning

Issue&Volume: 2022-11-09

Abstract: The heterogeneity of the tumour immune microenvironment (TIME), organized by various immune and stromal cells, is a major contributing factor of tumour metastasis, relapse and drug resistance1,2,3, but how different TIME subtypes are connected to the clinical relevance in liver cancer remains unclear. Here we performed single-cell RNA-sequencing (scRNA-seq) analysis of 189 samples collected from 124 patients and 8 mice with liver cancer. With more than 1million cells analysed, we stratified patients into five TIME subtypes, including immune activation, immune suppression mediated by myeloid or stromal cells, immune exclusion and immune residence phenotypes. Different TIME subtypes were spatially organized and associated with chemokine networks and genomic features. Notably, tumour-associated neutrophil (TAN) populations enriched in the myeloid-cell-enriched subtype were associated with an unfavourable prognosis. Through in vitro induction of TANs and ex vivo analyses of patient TANs, we showed that CCL4+ TANs can recruit macrophages and that PD-L1+ TANs can suppress T cell cytotoxicity. Furthermore, scRNA-seq analysis of mouse neutrophil subsets revealed that they are largely conserved with those of humans. In vivo neutrophil depletion in mouse models attenuated tumour progression, confirming the pro-tumour phenotypes of TANs. With this detailed cellular heterogeneity landscape of liver cancer, our study illustrates diverse TIME subtypes, highlights immunosuppressive functions of TANs and sheds light on potential immunotherapies targeting TANs.

DOI: 10.1038/s41586-022-05400-x

Source: https://www.nature.com/articles/s41586-022-05400-x