Melanoma is the solid tumor with high mutational burden, which leads the generation of neo-antigens and the infiltration of cytotoxic T cells (CTLs) recognizing these antigens. Recent improvement of prognosis of melanoma resulting from anti PD-1 antibody elucidated the importance of the expression of PD-1 on tumor-infiltrating CTLs for melanoma cells to evade the cytotoxic activity of CTLs. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that responds to a wide range of chemicals and induces the battery of genes associated with detoxification, including drug-metabolizing cytochrome P450s such as CYP1A1 or CYP1B1. Recently Liu and colleagues reported the upregulation of PD-1 on CTLs is, at least partly, induced via AHR activation induced by AHR ligands released from melanoma cells. Among various solid tumors, melanoma is known to exert the relatively stronger suppression to anti-tumor immunity. Notably, characteristic biology in melanoma compared to other solid tumors is the ability of melanogenesis, though little is known about the association between melanogenesis and anti-tumor immune response. Therefore, we investigated the correlation among melanogenesis, AHR activation and PD-1 expression level in the lesion of melanoma by using published RNA-seq data and immunohistochemistry of biopsy samples. Gene set variation analysis of RNA-seq data from microdissected lesions of nevus pigmentosus and malignant melanoma revealed the correlated variation between the gene set of AHR system and that of melanogenesis in melanoma. Moreover, immunohistochemical analysis revealed CYP1A1 is expressed in Tyrosinase+ melanoma cells and their surrounding CTLs, which are also tend to express PD-1. Furthermore, given the clinical data, the level of CYP1A1 expression in melanoma lesion tends to correlate with the efficacy of immunotherapies including anti PD-1 antibody. These results indicate the melanogenic property of melanoma cells enables them to activate AHR system, which suppresses anti-tumor immunity via the upregulation of PD-1 on CTLs in some way related to melanogenesis.

Melanogenic property of melanoma is associated with aryl hydrocarbon receptor-induced suppression of anti-melanoma immune response