DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma
Abstract Background Malignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underp...
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Springer
2025-03-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04012-4 |
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| author | Huilin Zhang Luanxue Yu Yunqing Guo Jiawei Ming Zhenying Guo |
| author_facet | Huilin Zhang Luanxue Yu Yunqing Guo Jiawei Ming Zhenying Guo |
| author_sort | Huilin Zhang |
| collection | DOAJ |
| description | Abstract Background Malignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underpinning mesothelioma’s progression remain insufficiently understood. HLA-C, a class I major histocompatibility complex (MHC) molecule, has been implicated in immune modulation and cancer progression, but its specific role in mesothelioma has yet to be thoroughly investigated. Methods This study employed a comprehensive multi-omics approach, integrating single-cell RNA sequencing, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR), to elucidate the role of HLA-C in mesothelioma progression. We first analyzed HLA-C expression within the TME, with particular focus on immune cells, especially macrophages. Survival analysis was conducted using data from the TCGA mesothelioma cohort to assess the clinical relevance of HLA-C expression. We utilized mediated MR analysis to investigate the impact of DNA methylation on HLA-C expression, identifying key mediators such as inflammatory cytokines, immune cell populations, blood cell types, and metabolites that could potentially influence patient prognosis. Results HLA-C was predominantly expressed in macrophages, T cells, and NK cells within the TME, and higher expression levels were associated with improved patient survival. MR analysis revealed that DNA methylation regulates HLA-C expression, which in turn impacts mesothelioma outcomes. Mediated MR analysis, encompassing 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types, and 1400 metabolites, highlighted several critical mediators of HLA-C’s effect on prognosis, including IL-10, CD33 expression on CD33dim HLA DR- myeloid cells, the reticulocyte perturbation response, and the ADP-to-citrate ratio. Gene set enrichment analysis (GSEA) showed significant enrichment of immune-related and inflammatory pathways in patients with high HLA-C expression. Conclusion HLA-C, regulated by DNA methylation, plays a central role in mesothelioma prognosis by modulating immune responses, inflammatory cytokines, blood cell populations, and metabolic processes within the TME. Our findings suggest that HLA-C could serve as both a prognostic biomarker and a potential therapeutic target for mesothelioma, offering new insights into the molecular mechanisms driving this aggressive cancer. |
| format | Article |
| id | doaj-art-742de290c9a341caacc3f908d2b7994f |
| institution | DOAJ |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-742de290c9a341caacc3f908d2b7994f2025-08-20T03:14:08ZengSpringerCancer Immunology, Immunotherapy1432-08512025-03-0174511310.1007/s00262-025-04012-4DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesotheliomaHuilin Zhang0Luanxue Yu1Yunqing Guo2Jiawei Ming3Zhenying Guo4Department of Surgical Pathology, School of Medicine, Women’s Hospital, Zhejiang UniversitySchool of Pharmacy, Hangzhou Normal UniversityJing Hengyi School of Education, Hangzhou Normal UniversitySchool of Public Health, Hangzhou Medical CollegeDepartment of Pathology, Cancer Center, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical CollegeAbstract Background Malignant mesothelioma is a highly aggressive cancer with a poor prognosis and limited therapeutic options. The tumor microenvironment (TME) plays a pivotal role in driving tumor progression, with immune cells influencing disease outcomes. However, the molecular mechanisms underpinning mesothelioma’s progression remain insufficiently understood. HLA-C, a class I major histocompatibility complex (MHC) molecule, has been implicated in immune modulation and cancer progression, but its specific role in mesothelioma has yet to be thoroughly investigated. Methods This study employed a comprehensive multi-omics approach, integrating single-cell RNA sequencing, expression quantitative trait loci (eQTL) analysis, and Mendelian randomization (MR), to elucidate the role of HLA-C in mesothelioma progression. We first analyzed HLA-C expression within the TME, with particular focus on immune cells, especially macrophages. Survival analysis was conducted using data from the TCGA mesothelioma cohort to assess the clinical relevance of HLA-C expression. We utilized mediated MR analysis to investigate the impact of DNA methylation on HLA-C expression, identifying key mediators such as inflammatory cytokines, immune cell populations, blood cell types, and metabolites that could potentially influence patient prognosis. Results HLA-C was predominantly expressed in macrophages, T cells, and NK cells within the TME, and higher expression levels were associated with improved patient survival. MR analysis revealed that DNA methylation regulates HLA-C expression, which in turn impacts mesothelioma outcomes. Mediated MR analysis, encompassing 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types, and 1400 metabolites, highlighted several critical mediators of HLA-C’s effect on prognosis, including IL-10, CD33 expression on CD33dim HLA DR- myeloid cells, the reticulocyte perturbation response, and the ADP-to-citrate ratio. Gene set enrichment analysis (GSEA) showed significant enrichment of immune-related and inflammatory pathways in patients with high HLA-C expression. Conclusion HLA-C, regulated by DNA methylation, plays a central role in mesothelioma prognosis by modulating immune responses, inflammatory cytokines, blood cell populations, and metabolic processes within the TME. Our findings suggest that HLA-C could serve as both a prognostic biomarker and a potential therapeutic target for mesothelioma, offering new insights into the molecular mechanisms driving this aggressive cancer.https://doi.org/10.1007/s00262-025-04012-4MesotheliomaHLA-CDNA methylationMendelian randomizationTumor microenvironment |
| spellingShingle | Huilin Zhang Luanxue Yu Yunqing Guo Jiawei Ming Zhenying Guo DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma Cancer Immunology, Immunotherapy Mesothelioma HLA-C DNA methylation Mendelian randomization Tumor microenvironment |
| title | DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma |
| title_full | DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma |
| title_fullStr | DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma |
| title_full_unstemmed | DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma |
| title_short | DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma |
| title_sort | dna methylation regulated hla c expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma |
| topic | Mesothelioma HLA-C DNA methylation Mendelian randomization Tumor microenvironment |
| url | https://doi.org/10.1007/s00262-025-04012-4 |
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