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

Forsthuber A, Aschenbrenner B, Korosec A, Jacob T, Annusver K, Krajic N, Kholodniuk D, Frech S, Zhu S, Purkhauser K, Lipp K, Werner F, Nguyen V, Griss J, Bauer W, Soler Cardona A, Weber B, Weninger W, Gesslbauer B, Staud C, Nedomansky J, Radtke C, Wagner SN, Petzelbauer P, Kasper M, Lichtenberger BM

Nat Commun 15 (1) 9678 [2024-11-08; online 2024-11-08]

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.

Bioinformatics Support for Computational Resources [Service]

PubMed 39516494

DOI 10.1038/s41467-024-53908-9

Crossref 10.1038/s41467-024-53908-9

pmc: PMC11549091
pii: 10.1038/s41467-024-53908-9