Clinical significance and immune landscape of KIR2DL4 and the senescence-based signature in cutaneous melanoma.

Senescence is an effective barrier to tumor progression. Mutations that inhibit senescence and promote cell division are mandatory for the development of cancer. Therefore, it is particularly important to explore the differences between cutaneous melanoma (CM) patients with severe and mild degrees of senescence. We clustered all the patients with CM in the Cancer Genome Atlas (TCGA) database based on all the genes of the senescence pathway in the CellAge and MSigDB database. The prognosis, immunotherapy effect, tumor microenvironment score, NRAS mutation rate, expression of CD274, CTLA4, and PDCD1, and abundance of CD8 T and natural killer (NK) cell infiltration in the younger group of patients (YG) were higher than those in the older group (OG). Compared with the American Joint Committee on Cancer (AJCC) stage, the risk scoring system stratified the risk of CM patients and guided immunotherapy more accurately. The nomogram model, which combined the AJCC stage and risk score, greatly improved the ability and accuracy of prognosis prediction. As KIR2DL4 is the core molecule in the risk scoring system (RSS), knocking down the KIR2DL4 of human NK cells in vitro can inhibit the cytotoxicity of NK cells and can also inhibit the secretion of tumor necrosis factor-α and interferon-γ by NK cells. In contrast, upregulation of KIR2DL4 can activate the MEK/ERK signaling pathway, which is the activation pathway of NK cells. Our RSS and nomogram model can accurately stratify the risk of CM patients and effectively predict the effect of immunotherapy and prognosis in CM patients.