Immunosuppressive Environment in Basal Cell Carcinoma: The Role of Regulatory T Cells

Abstract

Interaction between tumour survival tactics and anti-tumour immune response is a major determinant for cancer growth. Regulatory T cells (T-regs) contribute to tumour immune escape, but their role in basal cell carcinoma (BCC) is not understood. The fraction of T-regs among T cells was analysed by immunohistochemistry followed by automated image analysis in facial BCC, peritumoural skin and normal, buttock skin. Quantitative real-time PCR (qRT-PCR) was performed for FOXP3 and cytokines involved in T-reg attraction and T-cell activation. T-regs comprised 45% of CD4-cells surrounding BCC. FOXP3 was highly expressed in BCC, but absent in buttock skin. Unexpectedly, expression of FOXP3 was increased in peritumoural skin, with the FOXP3/CD3 fractions exceeding those of BCC (p?=?0.0065). Transforming growth factor (TGF)-? and T-reg chemokine expression was increased in BCC and peritumoural skin, but not in buttock skin, with expression levels correlating with FOXP3. T-regs are abundantly present both in BCC and in peritumoural skin, mediating an immunosuppressed microenvironment permissive for skin cancer.

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

“…In line with the expression of IL10 and TGFβ, we show increased numbers of Treg cells in Ptch Δep tumors, similar to human BCC, where Omland et al . [70] provided evidence that active HH/GLI signaling can induce Treg accumulation along with a strong increase of TGFβ expression. Furthermore, Hanna et al .…”

FOXP3 and CTLA-4 genetic variants’ influence on the susceptibility and clinical course of basal cell carcinoma

“…T regs have been previously recognized as one of the key elements modulating anti-tumour immunity and involved in the pathogenesis of numerous human neoplasia [1][2][3]. The population of T regs, which constitutes about 5% of CD4+ T lymphocytes, is characterized by high-intensity expression of CD25 and involves two main subsets [13].…”

“…The pathogenesis of basal cell carcinoma (BCC) is multifactorial and not fully elucidated. Previous studies showed that behaviour of the tumour may be influenced by the immune system and identified CD4 + CD25 + FoxP3 + regulatory T cells (T regs ) as dominant immune cells in BCC microenvironment [1][2][3]. It is known that different types of human cancer are able to recruit immune cells to the tumour site to promote escape from host immune surveillance.…”

Oncogenic GLI1 and STAT1/3 activation drives immunosuppressive tryptophan/kynurenine metabolism via synergistic induction of IDO1 in skin cancer cells

“…Further, IDO1 activation in melanoma has been demonstrated to recruit myeloid derived suppressor cells (MDSCs) via enhancing Treg numbers, thereby contributing to immune evasion and resistance to immunotherapy [43]. Intriguingly, HH/GLI-induced BCC not only display increased numbers of Treg cells [30,87] but have also been shown to be infiltrated by immunosuppressive MDSCs [33]. Together, these data suggest that targeting of HH and JAK-STAT signaling in combination with IDO1 blockers and ICB may be a promising therapeutic approach for HH-associated malignancies, as such a combination would possibly not only target the oncogenic drivers but also re-establish the anti-tumoral immune response with more durable therapeutic effects.…”