RESUMEN
Mononuclear phagocytes (MNPs) encompass dendritic cells, monocytes, and macrophages (MoMac), which exhibit antimicrobial, homeostatic, and immunoregulatory functions. We integrated 178,651 MNPs from 13 tissues across 41 datasets to generate a MNP single-cell RNA compendium (MNP-VERSE), a publicly available tool to map MNPs and define conserved gene signatures of MNP populations. Next, we generated a MoMac-focused compendium that revealed an array of specialized cell subsets widely distributed across multiple tissues. Specific pathological forms were expanded in cancer and inflammation. All neoplastic tissues contained conserved tumor-associated macrophage populations. In particular, we focused on IL4I1+CD274(PD-L1)+IDO1+ macrophages, which accumulated in the tumor periphery in a T cell-dependent manner via interferon-γ (IFN-γ) and CD40/CD40L-induced maturation from IFN-primed monocytes. IL4I1_Macs exhibited immunosuppressive characteristics through tryptophan degradation and promoted the entry of regulatory T cell into tumors. This integrated analysis provides a robust online-available platform for uniform annotation and dissection of specific macrophage functions in healthy and pathological states.
Asunto(s)
Células Dendríticas/inmunología , Expresión Génica/inmunología , Monocitos/inmunología , Transcriptoma/genética , Macrófagos Asociados a Tumores/inmunología , Artritis Reumatoide/inmunología , COVID-19/inmunología , Expresión Génica/genética , Perfilación de la Expresión Génica , Humanos , Interferón gamma/inmunología , L-Aminoácido Oxidasa/metabolismo , Cirrosis Hepática/inmunología , Macrófagos/inmunología , Neoplasias/inmunología , ARN Citoplasmático Pequeño/genética , Análisis de la Célula Individual , Linfocitos T Reguladores/inmunología , Transcriptoma/inmunologíaRESUMEN
We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of â¼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.
Asunto(s)
Carcinoma Hepatocelular/patología , Células Endoteliales/metabolismo , Microambiente Tumoral/genética , Adulto , Animales , Carcinoma Hepatocelular/genética , Línea Celular , Modelos Animales de Enfermedad , Células Endoteliales/patología , Femenino , Receptor 2 de Folato/metabolismo , Perfilación de la Expresión Génica/métodos , Humanos , Hígado/patología , Neoplasias Hepáticas/genética , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal/genética , Transcriptoma/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Tumors exhibit genetic and phenotypic diversity leading to intra-tumor heterogeneity (ITH). Further complex ecosystem (stromal and immune cells) of tumors contributes into the ITH. This ITH allows tumors to overcome various selection pressures such as anti-cancer therapies and metastasis at distant organs. Single-cell RNA-seq (scRNA-seq) has provided unprecedented insights into ITH and its implications in drug resistance and metastasis. As scRNA-seq technology grows and provides many new findings, new tools on different programming platforms are frequently generated. Here, we aim to provide a framework and guidelines for new entrants into the field of scRNA-seq. In this review, we discuss the current state-of-art of scRNA-seq analysis step-by-step including filtering, normalization and analysis. First, we discuss the brief history of experimental methods, followed by data processing and implications in precision oncology.