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
Translational Cancer Research Center, Peking University First Hospital, Beijing, China.
BIOPIC, Beijing Advanced Innovation Center for Genomics, School of Life Sciences, Peking University, Beijing, China.
Nature. 2022 Dec;612(7938):141-147. doi: 10.1038/s41586-022-05400-x. Epub 2022 Nov 9.
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 resistance, 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 1 million 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.
由各种免疫细胞和基质细胞构成的肿瘤免疫微环境（TIME）的异质性是肿瘤转移、复发和耐药的主要促成因素，但不同的TIME亚型与肝癌临床相关性之间的联系仍不清楚。在此，我们对从124例患者和8只患有肝癌的小鼠身上采集的189个样本进行了单细胞RNA测序（scRNA-seq）分析。在分析了超过100万个细胞后，我们将患者分为五种TIME亚型，包括免疫激活、由髓系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亚型在空间上有序分布，并与趋化因子网络和基因组特征相关。值得注意的是，在富含髓系细胞的亚型中富集的肿瘤相关中性粒细胞（TAN）群体与不良预后相关。通过体外诱导TAN以及对患者TAN进行离体分析，我们发现CCL4+TAN可以招募巨噬细胞，而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分析表明，它们在很大程度上与人类的亚群保守。在小鼠模型中进行体内中性粒细胞清除可减弱肿瘤进展，证实了TAN的促肿瘤表型。通过对肝癌这种详细的细胞异质性情况的研究，我们的研究阐明了不同的TIME亚型，突出了TAN的免疫抑制功能，并揭示了针对TAN的潜在免疫疗法。
