Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response

• Published in: Nature communications Vol. 15; no. 1; pp. 5665 - 14
• Main Authors: Coulton, Alexander, Murai, Jun, Qian, Danwen, Thakkar, Krupa, Lewis, Claire E., Litchfield, Kevin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 45/91; 631/250/2502; 631/250/2504/342; 631/250/580; 631/67/69; 692/4028/67/327; Cancer; Cell activation; Complexity; Gene Expression Regulation, Neoplastic; Gene mapping; Hepatocytes; Heterogeneity; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Immunotherapy - methods; Liver cancer; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Metastases; multidisciplinary; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Ontogeny; Phenotypes; Phenotypic variations; RNA-Seq; Science; Science (multidisciplinary); Single-Cell Analysis; T-Lymphocytes - immunology; Tumor Microenvironment - immunology; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49885-8

The paradigm for macrophage characterization has evolved from the simple M1/M2 dichotomy to a more complex model that encompasses the broad spectrum of macrophage phenotypic diversity, due to differences in ontogeny and/or local stimuli. We currently lack an in-depth pan-cancer single cell RNA-seq (scRNAseq) atlas of tumour-associated macrophages (TAMs) that fully captures this complexity. In addition, an increased understanding of macrophage diversity could help to explain the variable responses of cancer patients to immunotherapy. Our atlas includes well established macrophage subsets as well as a number of additional ones. We associate macrophage composition with tumour phenotype and show macrophage subsets can vary between primary and metastatic tumours growing in sites like the liver. We also examine macrophage-T cell functional cross talk and identify two subsets of TAMs associated with T cell activation. Analysis of TAM signatures in a large cohort of immune checkpoint inhibitor-treated patients (CPI1000 + ) identify multiple TAM subsets associated with response, including the presence of a subset of TAMs that upregulate collagen-related genes. Finally, we demonstrate the utility of our data as a resource and reference atlas for mapping of novel macrophage datasets using projection. Overall, these advances represent an important step in both macrophage classification and overcoming resistance to immunotherapies in cancer. Single cell sequencing can be used to examine tumour associated macrophages (TAM) and comparison between studies has been a challenge. Here the authors show a comparison tool to compare and contrast TAMs from different human tumour types and how these cells associate with T cells exploring further macrophage heterogeneity.