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A study at MedUni Vienna’s Department of Dermatology provides insights into the diversity of cancer-associated fibroblasts in white and black skin cancer and describes their different immunomodulatory roles in the tumor environment. The results are relevant for the development of novel skin cancer therapies, particularly in the field of immunotherapy.
Fibroblasts are specialized cells in connective tissues that play an important role in wound healing and tissue repair. They produce and organize the so-called extracellular matrix, a network of proteins such as collagen, which makes the tissue stable and elastic, but also perform many other tasks. Cancer-associated fibroblasts (CAFs) are an important component in solid tumors. They play a decisive role in cancer development and have a significant influence on the success of therapy. A study at MedUni Vienna’s Department of Dermatology was the first to investigate the previously unknown diversity of CAFs in various types of skin cancer — basal cell carcinoma, squamous cell carcinoma and melanoma — at molecular and spatial level in single-cell analysis.
Through a comprehensive study of fibroblasts in the tumor environment, including their interaction with other cells such as epithelial, mesenchymal and immune cells, three clearly distinguishable subtypes of CAFs (cancer-associated fibroblasts) were identified: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs) and immunomodulatory CAFs (iCAFs). It is particularly striking that the distribution of these subtypes changes with increasing aggressive of tumors.
Distinct subtypes with different roles in the tumor microenvironment
Two of these subtypes have the ability to influence the immune system, but in different ways. The mCAFs produce more matrix proteins and are often found at the tumor-stroma border in less aggressive tumors. They surround the tumor nests and may prevent immune cells such as T cells from invading the tumor. In contrast, iCAFs are increasingly found in aggressive forms of skin cancer (invasive basal cell carcinoma and high-grade melanoma). These cells produce large amounts of signaling factors (cytokines and chemokines) that play an important role in attracting and activating immune cells.
“Interestingly, it was shown that healthy fibroblasts that are exposed to the secretome of skin cancer cells in the laboratory develop a similar behavior to iCAFs and are capable of activating naive T cells,” says study leader Beate Lichtenberger from MedUni Vienna’s Department of Dermatology, describing the results, “this shows that it may be possible to target these subtypes.”
The results of this study are relevant for the development of novel skin cancer therapies, particularly in the field of immunotherapy. Beate Lichtenberger on the significance of the findings: “The targeted treatment of the various CAF subtypes, in particular the immunomodulatory iCAFs, could significantly improve the success of therapy by strengthening the immune response and limiting the spread of tumor cells. These new findings could provide the basis for innovative therapeutic approaches and make skin cancer treatments significantly more effective.”