Profiling the unique resident immune cell compartment in acral skin and its implications for acral melanoma tumor immunity

Acral melanoma is a rare and understudied form of melanoma that arises in either glabrous skin or the nail matrix and bears distinct characteristics from other cutaneous melanoma subtypes. The purpose of our study is to investigate biological underpinnings that may explain why acral melanomas have worse prognosis and worse response to therapy, including immunotherapy, when compared with other cutaneous melanoma subtypes in patients. It has been previously reported that the tumor microenvironment in acral melanoma is less infiltrated by T cells compared with other cutaneous melanomas subtypes. We hypothesized that the resident immune cells in non-tumor bearing skin may differ between skin sites and could help explain the downstream immune response to a tumor. To test this hypothesis, we obtained paired sets of non-tumor bearing glabrous (acral) and non-glabrous skin from a human donor and enzymatically treated them to enable mechanical separation of the epidermis from the dermis. We then profiled the resident immune cells in the epidermis and dermis separately by flow cytometry. We quantified T cells, macrophages, dendritic cells, and Langerhans cells and discovered a distinct cadre of immune cells at each site. We observed a dramatic reduction in the abundance of Langerhans cells in the epidermis at glabrous sites. Langerhans cells are skin-resident antigen presenting cells that play a critical role in immune surveillance, and reside in the epidermis, the same layer of the skin as melanocytes, the cell of origin of melanoma. These findings open new avenues for future investigation into how early immune surveillance by Langerhans cells to nascent melanomas may directly influence long-term tumor immunity in acral melanoma and its response to immunotherapy.