The heterogeneity of tumor immune microenvironment (TIME), organized by various immune and stromal cells, is a major cause of tumor metastasis and drug resistance, but how different TIME subtypes are connected to the clinical relevance in liver cancer remains elusive. Here, we performed single cell RNA-sequencing (scRNA-seq) on 189 samples collected from 124 patients and 8 mice with liver cancer. With over a million cells analyzed, we stratified patients into five TIME subtypes including immune activation, suppression mediated by myeloid or by stromal cells, exclusion, and residence phenotypes. Different TIME subtypes were spatially organized by specific cell populations, associated with chemokine networks and genomic features. Notably, within myeloid cell-enriched TIME subtype, tumor-associated neutrophil (TAN) populations were significantly associated with unfavorable prognosis. By in vitro induction of TANs and ex vivo analyses of patient TANs, we validated that CCL4+ TANs could recruit macrophages and PD-L1+ TANs could suppress T cell cytotoxicity. Further, in vivo neutrophil depletion in mouse models attenuated tumor progression, validating the pro-tumor 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 novel immunotherapies targeting TANs.
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Xue et al. Liver tumour immune microenvironment subtypes and neutrophil heterogeneity. Nature (2022).