Cancer-associated fibroblast subtypes modulate the tumor-immune microenvironment and are associated with skin cancer malignancy
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.
Authors
- Johannes Griss (ORCID: https://orcid.org/0000-0003-2206-9511)
- Franziska Werner (ORCID: https://orcid.org/0000-0002-1502-2259)
- Ana Cardona
- Vy Nguyen (ORCID: https://orcid.org/0000-0003-3436-3662)
- Agnes Forsthuber (ORCID: https://orcid.org/0000-0001-6396-0090)
- Bertram Aschenbrenner (ORCID: https://orcid.org/0000-0003-1177-7109)
- Christine Radtke (ORCID: https://orcid.org/0000-0001-6877-5038)
- Sophie Frech (ORCID: https://orcid.org/0000-0002-6190-8595)
- Ana Korosec (ORCID: https://orcid.org/0000-0001-6551-6727)
- Benedikt Weber (ORCID: https://orcid.org/0000-0002-7217-4590)
- Maria Kasper (ORCID: https://orcid.org/0000-0002-6117-2717)
- Beate M. Lichtenberger (ORCID: https://orcid.org/0000-0001-6882-0257)
- Jakob Nedomansky (ORCID: https://orcid.org/0000-0002-5090-1144)
- Natalia Krajic (ORCID: https://orcid.org/0000-0002-9255-5251)
- Wolfgang Michael Bauer (ORCID: https://orcid.org/0000-0002-0155-1176)
- Peter Petzelbauer (ORCID: https://orcid.org/0000-0001-7080-5259)
- Katharina Lipp (ORCID: https://orcid.org/0000-0002-3147-0916)
- Tina Jacob (ORCID: https://orcid.org/0000-0002-7180-2698)
- Bernhard Geßlbauer
- Clement Staud (ORCID: https://orcid.org/0000-0003-2771-8867)
- Stephan N. Wagner (ORCID: https://orcid.org/0000-0003-4941-7029)
- Kim Purkhauser (ORCID: https://orcid.org/0000-0003-1732-9673)
- Wolfgang J. Weninger (ORCID: https://orcid.org/0000-0003-0575-0073)
- Karl Annusver (ORCID: https://orcid.org/0000-0002-9515-7216)
- Shaohua Zhu
- Daria Kholodniuk
Institutions
- Karolinska Institutet (SE)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-08
- DOI
- https://doi.org/10.1038/s41467-024-53908-9
- Citations
- 74
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 17.56