Single-cell profiling of acral melanoma infiltrating lymphocytes reveals a suppressive tumor microenvironment

Sci Transl Med. 2024 Dec 4;16(776):eadk8832. doi: 10.1126/scitranslmed.adk8832. Epub 2024 Dec 4.

Abstract

Acral lentiginous melanoma (ALM) is the most common melanoma subtype in non-Caucasians. Despite advances in cancer immunotherapy, current immune checkpoint inhibitors remain unsatisfactory for ALM. Hence, we conducted comprehensive immune profiling using single-cell phenotyping with reactivity screening of the T cell receptors of tumor-infiltrating T lymphocytes (TILs) in ALM. Compared with cutaneous melanoma, ALM showed a lower frequency of tumor-reactive CD8 clusters and an enrichment of regulatory T cells with direct tumor recognition ability, suggesting a suppressive immune microenvironment in ALM. Tumor-reactive CD8 TILs showed heterogeneous expression of coinhibitory molecules, including KLRC1 (NKG2A), in subpopulations with therapeutic implications. Overall, our study provides a foundation for enhancing the efficacy of immunotherapy in ALM.

MeSH terms

  • CD8-Positive T-Lymphocytes / immunology
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating* / immunology
  • Lymphocytes, Tumor-Infiltrating* / metabolism
  • Male
  • Melanoma* / immunology
  • Melanoma* / pathology
  • Middle Aged
  • Single-Cell Analysis*
  • Skin Neoplasms / immunology
  • Skin Neoplasms / pathology
  • Tumor Microenvironment* / immunology