DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma

Our plain-English summary of DNA methylation-regulated HLA-C expression modulates immune responses and metabolic alterations to influence prognosis in mesothelioma, by H. Zhang, L. Yu, Y. Guo, et al (Cancer Immunology, Immunotherapy, 2025).

The study

• Authors: H. Zhang, L. Yu, Y. Guo, J. Ming, Z. Guo
• Journal: Cancer Immunology, Immunotherapy
• Published: 2025;74(5):158
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2025. The Author(s).

In plain English

This computer-based study re-analyzed public genetic and gene-expression datasets. It did not examine asbestos exposure. The authors studied HLA-C, an immune-system gene, in mesothelioma; the article does not specify the tumor site. In single-cell tumor data, HLA-C was mainly expressed in macrophages, and also in T cells and NK cells. In The Cancer Genome Atlas mesothelioma group, high HLA-C expression was associated with better survival than low expression, though the text gives no hazard ratios. The authors also used Mendelian randomization, a genetic method, with Finnish data on 442 mesothelioma patients and 378,749 controls. With it, they reported that DNA methylation at certain sites was linked to HLA-C levels and to outcome. Using mediation models, they estimated that part of HLA-C's effect ran through IL-10 (23.56%), CD33 on certain myeloid cells (CD33dim HLA DR- cells; over 10%), a laboratory measurement of reticulocytes (young red blood cells) after exposure to ciprofloxacin (16.14%) and the ADP-to-citrate ratio (12.01%). The authors concluded that HLA-C may be a prognostic marker and treatment target. They said laboratory studies and clinical trials are still needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Computational multi-omics analysis of existing public datasets: single-cell RNA sequencing, Mendelian randomization and mediation Mendelian randomization using genetic data (eQTL and methylation QTL), survival analysis, and gene set enrichment analysis
• Who was studied: Public datasets only. Genetic outcome data came from the Finnish R12 mesothelioma dataset (442 mesothelioma patients and 378,749 control subjects of European ancestry). Tumor single-cell data came from GSE190597. The TCGA mesothelioma cohort, of unstated size, was used for survival analysis, with validation in the GEO datasets GSE112154 and GSE29354. The tumor site of the mesotheliomas studied is not specified.
• Exposure: No asbestos or fiber exposure was studied. The factors analyzed were genetically predicted HLA-C gene expression and DNA methylation at HLA-C sites. The possible mediators examined were 91 inflammatory cytokines, 731 immune cell populations, 91 blood cell types and 1,400 plasma metabolites.
• Main results:
  • In single-cell data from mesothelioma tumors, HLA-C was mainly expressed in macrophages, with significant expression also in T cells and NK cells
  • In the TCGA mesothelioma cohort, high HLA-C expression (top 25% of samples) was significantly associated with better prognosis than low expression. No hazard ratio is given in the text.
  • Of 46 methylation sites linked to HLA-C, 14 were significantly associated with outcome. In mediation analysis, 10 sites affected outcome through HLA-C expression. The largest share was for cg01006124, which accounted for 95.78% of the effect.
  • Among inflammatory cytokines, IL-10 was estimated to mediate 23.56% of HLA-C's effect on mesothelioma prognosis, and CD6 6.22%
  • Among immune cell traits, only CD33 on CD33dim HLA DR- cells (a myeloid cell population) had a mediation proportion above 10%
  • A reticulocyte perturbation response, defined as the side scatter median of reticulocyte 1 after ciprofloxacin perturbation, was estimated to mediate 16.14% of HLA-C's effect
  • Of 13 metabolites regulated by HLA-C, only the ADP-to-citrate ratio showed a significant mediation effect, with a mediation proportion of 12.01%
  • In TCGA tumors, high HLA-C expression was associated with significant enrichment of immune-related pathways, including interferon signaling, IL-12 signaling and antigen presentation
  • In the two validation cohorts (GSE112154 and GSE29354), high HLA-C expression was linked to higher estimated immune cell abundances
• The authors' conclusion: The authors concluded that HLA-C, regulated by DNA methylation, may serve as a prognostic biomarker and a possible therapeutic target in mesothelioma
• Limitations the authors state:
  • The authors' proposal that HLA-C affects immune cell metabolism through cytokines such as IL-10 lacks direct evidence
  • The identified mediators (IL-10, CD33dim HLA DR- myeloid cells, ADP-to-citrate ratio) have not been functionally tested in laboratory or animal studies
  • The clinical usefulness of HLA-C as a biomarker or treatment target has not been tested in prospective trials

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Prognosis, Mesothelioma, Tumor Microenvironment, Macrophage, Cytokine, Biomarker.

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