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

Agnes Forsthuber, Bertram Aschenbrenner, Ana Korosec, Tina Jacob, Karl Annusver, Natalia Krajic, Daria Kholodniuk, Sophie Frech, Shaohua Zhu, Kim Purkhauser, Katharina Lipp, Franziska Werner, Vy Nguyen, Johannes Griss, Wolfgang Bauer, Ana Soler Cardona, Benedikt Weber, Wolfgang Weninger, Bernhard Gesslbauer, Clement Staud, Jakob Nedomansky, Christine Radtke, Stephan N. Wagner, Peter Petzelbauer, Maria Kasper () and Beate M. Lichtenberger ()
Additional contact information
Agnes Forsthuber: Medical University of Vienna
Bertram Aschenbrenner: Medical University of Vienna
Ana Korosec: Medical University of Vienna
Tina Jacob: Karolinska Institutet
Karl Annusver: Karolinska Institutet
Natalia Krajic: Medical University of Vienna
Daria Kholodniuk: Medical University of Vienna
Sophie Frech: Medical University of Vienna
Shaohua Zhu: Medical University of Vienna
Kim Purkhauser: Medical University of Vienna
Katharina Lipp: Medical University of Vienna
Franziska Werner: Medical University of Vienna
Vy Nguyen: Medical University of Vienna
Johannes Griss: Medical University of Vienna
Wolfgang Bauer: Medical University of Vienna
Ana Soler Cardona: Medical University of Vienna
Benedikt Weber: Medical University of Vienna
Wolfgang Weninger: Medical University of Vienna
Bernhard Gesslbauer: Medical University of Vienna
Clement Staud: Medical University of Vienna
Jakob Nedomansky: Medical University of Vienna
Christine Radtke: Medical University of Vienna
Stephan N. Wagner: Medical University of Vienna
Peter Petzelbauer: Medical University of Vienna
Maria Kasper: Karolinska Institutet
Beate M. Lichtenberger: Medical University of Vienna

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-53908-9

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