Myofibroblast stroma differentiation in infiltrative basal cell carcinoma is accompanied by regulatory T-cells

Introduction: The implications of infiltrative compared to non-infiltrative growth of cutaneous basal cell carcinoma (BCC) on the tumor stroma and immune cell landscape are unknown. This is of clinical importance, because infiltrative BCCs, in contrast to other BCC subtypes, are more likely to relapse after surgery and radiotherapy.

Materials and methods: This descriptive cross-sectional study analyzed 38 BCCs collected from 2018 to 2021. In the first cohort (n = 28), immune cells were characterized by immunohistochemistry and multiplex immunofluorescence staining for CD3, CD8, CD68, Foxp3, and α-SMA protein expression. In the second cohort (n = 10) with matched characteristics (age, sex, location, and BCC subtype), inflammatory parameters, including TGF-β1, TGF-β2, ACTA2, IL-10, IL-12A, and Foxp3, were quantified via RT-qPCR after isolating mRNA from BCC tissue samples and perilesional skin.

Results: Infiltrative BCCs showed significantly increased levels of α-SMA expression in fibroblasts (p = 0.0001) and higher levels of Foxp3+ (p = 0.0023) and CD3+ (p = 0.0443) T-cells compared to non-infiltrative BCCs. CD3+ (p = 0.0171) and regulatory T-cells (p = 0.0026) were significantly increased in α-SMA-positive tumor stroma, whereas CD8+ T-cells (p = 0.1329) and CD68+ myeloid cells (p = 0.2337) were not affected. TGF-β1 and TGF-β2 correlated significantly with ACTA2/α-SMA mRNA expression (p = 0.020, p = 0.005).

Conclusion: Infiltrative growth of BCCs shows a myofibroblastic stroma differentiation and is accompanied by an immunosuppressive tumor microenvironment.