Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy

• Published in: Nature communications 2024-11, Vol.15 (1), p.9678-20, Article 9678
• Main Authors: Forsthuber, Agnes, Aschenbrenner, Bertram, Korosec, Ana, Jacob, Tina, Annusver, Karl, Krajic, Natalia, Kholodniuk, Daria, Frech, Sophie, Zhu, Shaohua, Purkhauser, Kim, Lipp, Katharina, Werner, Franziska, Nguyen, Vy, Griss, Johannes, Bauer, Wolfgang, Soler Cardona, Ana, Weber, Benedikt, Weninger, Wolfgang, Gesslbauer, Bernhard, Staud, Clement, Nedomansky, Jakob, Radtke, Christine, Wagner, Stephan N., Petzelbauer, Peter, Kasper, Maria, Lichtenberger, Beate M.
• Format: Article
• Language: English
• Subjects: 13; 13/106; 13/31; 14/19; 14/32; 14/63; 38; 38/88; 38/91; 631/67/580; 64; 692/4028/67/1813; 692/4028/67/327; Basal cell carcinoma; Cancer; Cancer-Associated Fibroblasts - immunology; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Basal Cell - genetics; Carcinoma, Basal Cell - immunology; Carcinoma, Basal Cell - metabolism; Carcinoma, Basal Cell - pathology; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Cell activation; Cell Line, Tumor; Chemokines; Cytokines - metabolism; Extracellular matrix; Extracellular Matrix - immunology; Extracellular Matrix - metabolism; Fibroblasts; Heterogeneity; Humanities and Social Sciences; Humans; Immune system; Immunomodulation; Immunotherapy; Lymphocytes; Lymphocytes T; Malignancy; Melanoma; Melanoma - genetics; Melanoma - immunology; Melanoma - pathology; multidisciplinary; Phenotypes; Science; Science (multidisciplinary); Single-Cell Analysis; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - immunology; Skin Neoplasms - pathology; Spatial analysis; Squamous cell carcinoma; Tissue analysis; Transcriptomics; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53908-9

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers. Fibroblast heterogeneity in the tumor microenvironment can explain their multifaceted role in cancer. Here by single-cell transcriptomic analysis of basal cell carcinoma, squamous cell carcinoma and melanoma samples, the authors explore fibroblast heterogeneity in skin cancer and their potential to modulate the tumor-immune microenvironment.