HLA-G, cytokines, and cytokine receptors in the non-aggressive basal cell carcinoma microenvironment

Abstract

Non-aggressive basal cell carcinoma (BCC) growth is slow and might be mediated by the immune system. This study analysed the human leukocyte antigen (HLA)-G expression and cytokine profile in non-aggressive BCC subtypes from distinct locations. HLA-G was evaluated via immunohistochemistry and cytokine expression was analysed by a quantitative real-time polymerase chain reaction in 26 primary BCC samples, including nodular BCC (nBCC, n = 16) and superficial BCC (n = 10) from cephalic (ceBCC, n = 12) and non-cephalic (n = 14) locations, and by bioinformatics analysis of public GEO databases. Inflammatory infiltrate was concentrated around the tumour nests. HLA-G-positive inflammatory cells (53.85%) were more abundant than HLA-G-positive tumour cells (21.54%, p < 0.001). HLA-G immunoreactivity was predominantly cytoplasmic in BCC cells and was primarily associated with lymphocytes and macrophages surrounding the tumour. nBCC showed a higher percentage of HLA-G-positive tumour cells (p = 0.04), and ceBCC showed stronger intensity (p = 0.04). IFN-gamma and IL-10 expression were 1.95 and 1.22-fold higher, respectively, relative to that in normal skin, with a positive correlation between them (r = 0.61; p = 0.002). IL-23 expression was higher in nBCC (p = 0.04) and positively correlated (r = 0.47; p = 0.05) with slight intensity of HLA-G-positive tumour cells. The up-regulation of IL23A and IL10RB and down-regulation of IFNGR1 and IL4R gene expression in BCC compared to levels in adjacent tissues were demonstrated in the GSE125285 dataset. The exhibited cytokine profile was consistent with the induction of HLA-G expression in non-aggressive BCC subtypes. HLA-G expression in tumour cells and inflammatory cells surrounding BCCs supports the generation of inhibitory signals on various immune cells that exert anti-tumour responses.