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

提吉特 黑色素瘤 免疫系统 CD8型 浆细胞样树突状细胞 免疫疗法 癌症研究 免疫检查点 免疫学 生物 T细胞 细胞 医学
作者
Jiannong Li,Inna Smalley,Zhihua Chen,Jheng-Yu Wu,Manali S Phadke,James J. Mulé,Thanh Nguyen,Florian A. Karreth,John M. Koomen,Amod A Sarnaik,Jonathan S. Zager,Nikhil I Khushalani,A.A. Tarhini,Vernon K. Sondak,Paulo C. Rodriguez,Jane L. Messina,Yian Ann Chen,Keiran S.M. Smalley
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
标识
DOI:10.1158/1078-0432.ccr-21-3145
摘要

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.
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