Tolerogenic Monocyte-Derived Langerhans Cells Promote Melanoma Progression and Immunotherapy Resistance through Aryl Hydrocarbon Receptor-Cyclooxygenase-2 Activation

Abstract

Langerhans cells (LCs), as epidermal-resident antigen-presenting cells, are among the first to encounter early carcinogenic changes in the skin, such as those seen in melanoma. During inflammation or cancer, circulating monocytes are recruited into the epidermis, replacing resident LCs that have migrated to draining lymph nodes. However, the specific roles of LC subsets in the progression of melanoma remain unclear. In this study, we observed a decrease in resident LCs and an increase in monocyte-derived LCs (moLCs) within melanoma tumor tissues as the disease progressed. Notably, the frequency of moLCs was higher in patients with anti-PD-1 therapy-resistant melanoma than in those responsive to the therapy. Using muLangerin-DTR transgenic and moLC-specific knockout mouse models, we demonstrated that the depletion of resident LCs accelerated melanoma growth, whereas the depletion of moLCs suppressed tumor progression. Mechanistically, moLCs exhibited elevated expression of cyclooxygenase-2-related genes compared with resident LCs. TGF-β was found to activate aryl hydrocarbon receptor-cyclooxygenase-2 signaling in moLCs, leading to increased production of prostaglandin E₂ and expression of PD-L1, which collectively contributed to the immunosuppressive effects of moLCs on CD8⁺ cytotoxic T lymphocytes. In summary, our findings highlight the functional heterogeneity of LC subsets in melanoma progression, offering deeper insights into LC biology and potential therapeutic strategies.

Keywords: Immunity; Melanoma; TGF-β; moLC; rLC.