Comprehensive Pan-cancer Analysis of CMPK2 as Biomarker and Prognostic Indicator for Immunotherapy.

Abstract

Background: UMP-CMP kinase 2 (CMPK2) is involved in mitochondrial DNA synthesis, which can be oxidized and released into the cytoplasm in innate immunity. It initiates the assembly of NLRP3 inflammasomes and mediates various pathological processes such as human immunodeficiency virus infection and systemic lupus erythematosus. However, the role of CMPK2 in tumor progression and tumor immunity remains unclear.

Methods: We identified CMPK2 expression patterns in the Genotype Tissue-Expression (GTEx), The Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia (CCLE) databases. Validation was performed using immunohistochemical staining data from the Human Protein Atlas (HPA) database and qPCR experiments. Receiver operating characteristic curve analysis and Kaplan-Meier survival analysis were conducted to assess the clinical relevance of CMPK2 expression. The Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) algorithm and the Tumor IMmune Estimation Resource (TIMER) database were used to evaluate the correlation between CMPK2 and immune infiltration in tumors. The Tumor Immune Syngeneic Mouse (TISMO) database and other public datasets were utilized to assess the impact of CMPK2 on immune therapy response. MEXPRESS and MethSurv databases were employed to investigate the effects of methylation on CMPK2 expression.

Results: CMPK2 expression was elevated in 23 cancers and decreased in two cancers. Furthermore, CMPK2 expression had a high diagnostic value for 16 cancers. Elevated CMPK2 expression was associated with lower overall survival (OS), disease-specific survival (DSS), and progression- free interval (PFI) in four cancers. Immune microenvironment-related analysis revealed strong associations between CMPK2 expression and immune cell infiltration, as well as immune checkpoint expression across various tumors. Notably, in four mouse immunotherapy cohorts, CMPK2 expression in treated mouse tumors was higher post-treatment. In five clinical immunotherapy cohorts, patients with high CMPK2 expression show better responses to immunotherapy. Moreover, the methylation level of CMPK2 gene was closely correlated to its expression and tumor prognosis. Among these cancers, the clinical and immunological indications of skin cutaneous melanoma (SKCM) are particularly closely related to CMPK2 expression.

Conclusion: Our analysis preliminarily describes the complex function of CMPK2 in cancer progression and immune microenvironment, highlighting its potential as a diagnostic and therapeutic target for immunotherapy.