PMID- 36263038 OWN - NLM STAT- MEDLINE DCOM- 20221021 LR - 20221024 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - Distinct responses of newly identified monocyte subsets to advanced gastrointestinal cancer and COVID-19. PG - 967737 LID - 10.3389/fimmu.2022.967737 [doi] LID - 967737 AB - Monocytes are critical cells of the immune system but their role as effectors is relatively poorly understood, as they have long been considered only as precursors of tissue macrophages or dendritic cells. Moreover, it is known that this cell type is heterogeneous, but our understanding of this aspect is limited to the broad classification in classical/intermediate/non-classical monocytes, commonly based on their expression of only two markers, i.e. CD14 and CD16. We deeply dissected the heterogeneity of human circulating monocytes in healthy donors by transcriptomic analysis at single-cell level and identified 9 distinct monocyte populations characterized each by a profile suggestive of specialized functions. The classical monocyte subset in fact included five distinct populations, each enriched for transcriptomic gene sets related to either inflammatory, neutrophil-like, interferon-related, and platelet-related pathways. Non-classical monocytes included two distinct populations, one of which marked specifically by elevated expression levels of complement components. Intermediate monocytes were not further divided in our analysis and were characterized by high levels of human leukocyte antigen (HLA) genes. Finally, we identified one cluster included in both classical and non-classical monocytes, characterized by a strong cytotoxic signature. These findings provided the rationale to exploit the relevance of newly identified monocyte populations in disease evolution. A machine learning approach was developed and applied to two single-cell transcriptome public datasets, from gastrointestinal cancer and Coronavirus disease 2019 (COVID-19) patients. The dissection of these datasets through our classification revealed that patients with advanced cancers showed a selective increase in monocytes enriched in platelet-related pathways. Of note, the signature associated with this population correlated with worse prognosis in gastric cancer patients. Conversely, after immunotherapy, the most activated population was composed of interferon-related monocytes, consistent with an upregulation in interferon-related genes in responder patients compared to non-responders. In COVID-19 patients we confirmed a global activated phenotype of the entire monocyte compartment, but our classification revealed that only cytotoxic monocytes are expanded during the disease progression. Collectively, this study unravels an unexpected complexity among human circulating monocytes and highlights the existence of specialized populations differently engaged depending on the pathological context. CI - Copyright (c) 2022 Rigamonti, Castagna, Viatore, Colombo, Terzoli, Peano, Marchesi and Locati. FAU - Rigamonti, Alessandra AU - Rigamonti A AD - Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy. AD - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. FAU - Castagna, Alessandra AU - Castagna A AD - Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy. FAU - Viatore, Marika AU - Viatore M AD - Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy. FAU - Colombo, Federico Simone AU - Colombo FS AD - Flow Cytometry Core, IRCCS Humanitas Research Hospital, Milan, Italy. FAU - Terzoli, Sara AU - Terzoli S AD - Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Italy. FAU - Peano, Clelia AU - Peano C AD - Genomic Unit, IRCCS Humanitas Research Hospital, Milan, Italy. AD - Institute of Genetic and Biomedical Research, UoS of Milan, National Research Council, Milan, Italy. FAU - Marchesi, Federica AU - Marchesi F AD - Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy. AD - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. FAU - Locati, Massimo AU - Locati M AD - Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy. AD - Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20221003 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Immunologic Factors) RN - 9008-11-1 (Interferons) RN - 0 (HLA Antigens) SB - IM MH - Humans MH - Monocytes MH - *COVID-19 MH - Immunologic Factors/metabolism MH - *Gastrointestinal Neoplasms MH - Interferons/metabolism MH - HLA Antigens/metabolism PMC - PMC9576306 OTO - NOTNLM OT - COVID-19 OT - cancer OT - immunotherapy OT - machine learning OT - monocyte OT - single-cell transcriptome COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/10/21 06:00 MHDA- 2022/10/22 06:00 PMCR- 2022/10/03 CRDT- 2022/10/20 02:52 PHST- 2022/06/13 00:00 [received] PHST- 2022/08/16 00:00 [accepted] PHST- 2022/10/20 02:52 [entrez] PHST- 2022/10/21 06:00 [pubmed] PHST- 2022/10/22 06:00 [medline] PHST- 2022/10/03 00:00 [pmc-release] AID - 10.3389/fimmu.2022.967737 [doi] PST - epublish SO - Front Immunol. 2022 Oct 3;13:967737. doi: 10.3389/fimmu.2022.967737. eCollection 2022.