Single cell characterization of the cellular landscape of acral melanoma identifies novel targets for immunotherapy.

Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles and nail beds. In this study, we used single cell RNA-seq (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets.We performed scRNA-seq on 9 clinical specimens (5 primary, 4 metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of TCGA and single cell datasets. Cell-cell interactions were inferred and compared to those in non-acral cutaneous melanoma.Multiple phenotypic subsets of T cells, NK cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells and a near-complete absence of γδ T cells compared to non-acral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, VISTA, TIGIT and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells.Acral melanoma has a suppressed immune environment compared to that of cutaneous melanoma from non-acral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation.