Crosstalk of four kinds of cell deaths defines subtypes of cutaneous melanoma for precise immunotherapy and chemotherapy

BACKGROUND: Cell death patterns can give therapeutic and biological clues that facilitate the development of individualized treatments for this lethal form of skin cancer. METHODS: We employed unsupervised clustering to establish robust classifications based on the four kinds of cell death-associated gene expression of 462 melanoma patients in the Cancer Genome Atlas (TCGA) and tested their reproducibility in two independent melanoma cohorts of 558 patients. We then used dimensionality reduction of graph learning to display the different characteristics of cell death patterns and immune microenvironments. RESULTS: We examined 570 cell death-associated gene expression data of melanoma patients for exploration, independent verification, and comprehensive classification of five reproducible melanoma subtypes (CS1 to CS5) with different genomic and clinical features. Patients in death-inactive subtypes (CS1, CS2, and CS5) had the least immune and stromal cell infiltration, and their prognosis was the poorest. A death-active subtype (CS4), on the other hand, had the highest infiltrated immune and stromal cells and elevated immune-checkpoints. As a result, these patients had the highest response to immunotherapy and the best prognosis. An additional subtype (CS3) had more diversified cell death and immune characteristics with moderate prognoses. Based on graph learning, we successfully divided the CS3 subtype into two subgroups (group A and group B) with distinct survival outcomes and immune features. Finally, we identified eight potential chemical drugs that were specifically targeted for the therapy of melanoma subtypes. CONCLUSIONS: This research defines the intrinsic subtypes of melanoma based on the crosstalk of four kinds of cell deaths, which affords a blueprint for clinical strategies and guiding precise immunotherapy and chemotherapy for melanoma patients.