Abstract
Background: Killer Cell Lectin Like Receptor D1 (KLRD1) plays a crucial role in antitumor immunity. However, its expression patterns across various cancers, its relationship with patient prognosis, and its potential as an immunotherapy target remain inadequately understood. Methods: We analyzed KLRD1 expression across various cancer types using multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases, correlating it with patient prognosis. Single-cell RNA sequencing data were employed to further explore KLRD1 expression in natural killer (NK) cells and exhausted CD8+ T cells (CD8Tex). Functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) identified the biological processes and pathways associated with KLRD1. Immune infiltration analysis, conducted via CIBERSORT, assessed the relationship between KLRD1 expression and immune cell infiltration within the tumor microenvironment. Furthermore, the Tracking Tumor Immunophenotype (TIP) meta-server and Easier tool were employed to assess the role of KLRD1 in the cancer immunity cycle and to predict immunotherapy responses. Drug sensitivity was predicted using tools like CellMiner and the Genomics of Drug Sensitivity in Cancer (GDSC) database to explore the link between KLRD1 expression and responsiveness to various anticancer drugs. Results: KLRD1 exhibits significant differential expression and strong prognostic value across cancers, particularly as an independent prognostic factor in head and neck squamous cell carcinoma (HNSC). Single-cell analysis revealed high expression of KLRD1 in NK and CD8Tex cells, indicating its critical role in antitumor immune responses. Functional enrichment analyses showed that KLRD1 is involved in several immune-related signaling pathways, including NK cell-mediated cytotoxicity and T cell receptor pathways. Immune infiltration analysis further confirmed a positive correlation between KLRD1 expression and the infiltration of various immune cells. Moreover, higher KLRD1 expression in HNSC is associated with enhanced immune pathway activity, increased sensitivity to cell division inhibitors, and the identification of arachidonyltrifluoromethane as a potential compound to counteract its oncogenic effects. Conclusion: In HNSC, KLRD1 is a key prognostic marker and potential target for personalized immunotherapy.