Melanoma is a malignant tumor derived from pigment-producing melanocytes. In the past decades, the incidence of melanoma has increased rapidly. Melanoma is highly immunogenic and therefore suitable for immunotherapy, but the efficacy is limited by response rate. In several types of tumor, Tumor Mutation Burdens (TMB) and immune infiltration have been reported to predict the response to immunotherapy, although each has its limitations. In the current study, we aimed to explore the association of TMB with immune infiltration and prognosis in cutaneous melanoma. In the United States, melanoma is now estimated as the fifth most common cancer, and the probability of developing melanoma in a lifetime is 1 in 63. Early-stage melanomas have a good prognosis after surgery, but even relatively small melanomas have metastatic potential because of the loss of cellular adhesion. Prior to 2011, chemotherapy was regarded as the standard treatment for metastatic melanoma, with a 5-year survival rate of 15.7%. Fortunately, melanoma is one of the most immunogenic tumors and therefore has the greatest potential for response to immunotherapy, so it has been the most important tumor driving the development of solid tumor immunotherapy, especially Immune Checkpoint Inhibitors (ICIs) targeting such as programmed cell death protein 1 (PD-1), PD-1 ligand (PD-L1), and Cytotoxic T Lymphocyte Antigen 4 (CTLA4). ICIs have greatly improved the survival of patients with advanced melanoma. In recent clinical trials, the 5-year survival rate treated with pembrolizumab and a combination of nivolumab and ipilimumab in advanced melanoma was 34 and 52%, respectively.

omega replica watches

Considering the different therapeutic efficacy among patients, it is necessary to predict the response to immunotherapy. Although PD-L1 immunohistochemistry is the most widely used test to estimate the treatment response to ICIs, it has no influence on the treatment decision in most cases. Since melanocytes are usually exposed to a large amount of ultraviolet radiation and the accumulated mutations, melanomas have a higher mutational load than other tumors, which may increase the efficacy of ICIs by generating and presenting immunogenic neoantigens. Studies have found that predicting the response to immunotherapy through the overall mutational load may serve as a new perspective.

Tumor Mutation Burden (TMB), defined as the total number of somatic coding errors, base substitutions, and indel mutations per million bases, can effectively estimate overall mutational load and neoantigenic load. Besides, many studies discovered that TMB can be used as a biomarker to predict the response to immunotherapy and the efficacy of ICIs in many cancer types including melanoma. However, few studies have focused on the TMB-related immune cell infiltration and gene signature in melanoma, so we conducted the current study to explore the prognostic role of TMB and its association with immune infiltration and gene signature in melanoma.

In the current study, based on the data of cutaneous melanoma from The Cancer Genome Atlas (TCGA) database, we explored the correlation between TMB and prognosis, Differentially Expressed Genes (DEGs) between high- and low-TMB groups, the functional enrichment of DEGs, and the association of TMB with immune infiltration. Additionally, we constructed a risk score model according to TMB-related gene signature, completed the verification in three Gene Expression Omnibus (GEO) datasets, and developed a nomogram in combination with clinical characteristics. In cutaneous melanoma, higher TMB was associated with better survival outcomes. TMB-related DEGs were mainly involved in immune-related and cell adhesion-related pathways. The risk score model and nomogram had relatively high predictive capability on survival outcomes. The relationship between TMB and immune infiltration, especially the abundance of macrophages and Tregs, can provide a reference for further advanced prediction models of response to immunotherapy.

For more visit our home page: Journal of Clinical and Experimental Dermatology Research