Liver tumour immune microenvironment subtypes and neutrophil heterogeneity

Ruidong Xue, Qiming Zhang, Qi Cao, Ruirui Kong, Xiao Xiang, Hengkang Liu, Mei Feng, Fangyanni Wang, Jinghui Cheng, Zhao Li, Qimin Zhan, Mi Deng, Jiye Zhu (), Zemin Zhang () and Ning Zhang ()
Additional contact information
Ruidong Xue: Peking University First Hospital
Qiming Zhang: Peking University
Qi Cao: Peking University First Hospital
Ruirui Kong: Peking University First Hospital
Xiao Xiang: Peking University People’s Hospital
Hengkang Liu: Peking University First Hospital
Mei Feng: Peking University First Hospital
Fangyanni Wang: Peking University First Hospital
Jinghui Cheng: Peking University First Hospital
Zhao Li: Peking University People’s Hospital
Qimin Zhan: Peking University Health Science Center
Mi Deng: Peking University Health Science Center
Jiye Zhu: Peking University People’s Hospital
Zemin Zhang: Peking University
Ning Zhang: Peking University First Hospital

Nature, 2022, vol. 612, issue 7938, 141-147

Abstract: 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 resistance1–3, 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 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.

Date: 2022
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DOI: 10.1038/s41586-022-05400-x

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