Abstract
NLRC5 is an important regulator in antigen presentation and inflammation, and its dysregulation promotes tumor progression. In melanoma, the impact of NLRC5 expression on molecular phenotype, clinical characteristics, and tumor features is largely unknown. In the present study, public datasets from the Cancer Cell Line Encyclopedia (CCLE), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and cBioPortal were used to address these issues. We identify that NLRC5 is expressed in both immune cells and melanoma cells in melanoma samples and its expression is regulated by SPI1 and DNA methylation. NLRC5 expression is closely associated with Breslow thickness, Clark level, recurrence, pathologic T stage, and ulceration status in melanoma. Truncating/splice mutations rather than missense mutations in NLRC5 could compromise the expression of downstream genes. Low expression of NLRC5 is associated with poor prognosis, low activity of immune-related signatures, low infiltrating level of immune cells, and low cytotoxic score in melanoma. Additionally, NLRC5 expression correlates with immunotherapy efficacy in melanoma. In summary, these findings suggest that NLRC5 acts as a tumor suppressor in melanoma via modulating the tumor immune microenvironment. Targeting the NLRC5 related pathway might improve efficacy of immunotherapy for melanoma patients.
Highlights
Melanoma is a lethal form of skin cancer, with more than 320,000 patients diagnosed with melanoma and 57,043 deaths in 2020 globally (Sung et al, 2021)
We explored the biological processes (BPs) and HALLMARKs correlating with NLRC5 expression in melanoma through Gene Set Enrichment Analysis (GSEA) (Gene set enrichment analysis)
The analysis revealed that NLRC5 expression was significantly associated with the infiltrating level of T cells, CD8+ T cells, NK cells, B cells, monocytes, dendritic cells, and the ratio of macrophage/monocyte, but not neutrophils, endothelial cells, and cancer-associated fibroblasts (CAFs) (Table 2)
Summary
Melanoma is a lethal form of skin cancer, with more than 320,000 patients diagnosed with melanoma and 57,043 deaths in 2020 globally (Sung et al, 2021). Identifying characteristics of the patients for predicting who could benefit from immunotherapy is a key question It could avoid possible side effects and reduce medical costs for patients who are unsuitable to receive these kinds of treatment. NLRC5 has been identified to be an important transactivator for MHC class I genes (Yoshihama et al, 2017). The expression of NLRC5 correlates positively with the expression of MHC class I genes both in cell lines and tissues (Meissner et al, 2010; Neerincx et al, 2012; Staehli et al, 2012). NLRC5-deficient mice exhibit reduced expression of MHC class I genes (Biswas et al, 2012; Staehli et al, 2012; Yao et al, 2012). The value of NLRC5 expression in prediction of response to immunotherapy in melanoma was assessed
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