Identification of Potential Antigens for Developing mRNA Vaccine for Immunologically Cold Mesothelioma

Our plain-English summary of Identification of Potential Antigens for Developing mRNA Vaccine for Immunologically Cold Mesothelioma, by S. Zhang, S. Li, Y. Wei, et al (Frontiers in Cell and Developmental Biology, 2022).

The study

• Authors: S. Zhang, S. Li, Y. Wei, Y. Xiong, Q. Liu, Z. Hu, Z. Zeng, F. Tang, Y. Ouyang
• Journal: Frontiers in Cell and Developmental Biology
• Published: 2022;10:879278
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Messenger RNA vaccines are considered to be a promising strategy in cancer immunotherapy, while their application on mesothelioma is still largely uncharacterized. This study aimed to identify potential antigens in mesothelioma for anti-mesothelioma mRNA vaccine development, and further determine the immune subtypes of mesothelioma for selection of suitable candidates from an extremely heterogeneous population. Gene expression data and corresponding clinicopathological information were obtained from the TCGA and gene expression omnibus, respectively. Then, the genetic alterations were compared and visualized using cBioPortal, and differentially expressed genes and their prognostic signatures were identified by GEPIA. The relationship between tumor-infiltrating immune cells and the expression of tumor antigens was systematically evaluated by TIMER online. Finally, the immune subtypes and immune landscape of mesothelioma were separately analyzed using consensus cluster and graph learning-based dimensional reduction. A total of five potential tumor antigens correlated with prognosis and infiltration of antigen-presenting cells, including AUNIP, FANCI, LASP1, PSMD8, and XPO5 were identified. Based on the expression of immune-related genes, patients with mesothelioma were divided into two immune subtypes (IS1 and IS2). Each subtype exhibited differential molecular, cellular and clinical properties. Patients with the IS1 subtype were characterized by an immune "cold" phenotype, displaying superior survival outcomes, whereas those with the IS2 subtype were characterized by an immune "hot" and immunosuppressive phenotype. Furthermore, immune checkpoints and immunogenic cell death modulators were differentially expressed between the IS1 and IS2 immune subtype tumors. The immunogenomic landscape of mesothelioma revealed a complex tumor immune microenvironment between individual patients. AUNIP, FANCI, LASP1, PSMD8, and XPO5 are putative antigens for the development of anti-mesothelioma mRNA vaccine and patients with the IS1 subtype may be considered for vaccination.

Copyright © 2022 Zhang, Li, Wei, Xiong, Liu, Hu, Zeng, Tang and Ouyang.

In plain English

This was a computer-based analysis of publicly available tumor gene data. No patients were treated, and no vaccine was made or tested. The authors used data on 86 mesothelioma cases from The Cancer Genome Atlas as a discovery group and 131 cases from a Gene Expression Omnibus dataset (GSE163720) as a validation group. The article did not examine asbestos or any other exposure. By looking for genes that were both amplified and mutated, the authors identified five candidate targets for a possible mRNA vaccine: AUNIP, FANCI, LASP1, PSMD8 and XPO5. Higher expression of these genes was associated with poorer overall and relapse-free survival. Four of them were linked to higher levels of certain immune cells in tumors. Using 2,108 immune-related genes, the authors sorted patients into two immune subtypes. IS1, described as immune "cold", had better survival than IS2, described as immune "hot" and immunosuppressive. The two subtypes did not differ notably in tumor mutational burden. The authors concluded that the five genes are putative vaccine antigens and that IS1 patients could be more suitable for vaccination. They stated that further experiments, including mouse models, are needed to validate these findings.

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: Bioinformatics (computational) analysis of public gene expression and clinical databases; no laboratory, animal or clinical testing
• Who was studied: Mesothelioma tumor samples from public databases: 86 cases from The Cancer Genome Atlas (discovery cohort) and 131 cases from Gene Expression Omnibus dataset GSE163720 (validation cohort). TCGA patients with incomplete clinical information or survival under 90 days were excluded.
• Exposure: Not studied. The article analyzes gene expression in mesothelioma tumors and does not address asbestos or any fiber exposure.
• Main results:
  • Among amplified and mutated genes, 36 were significantly correlated with overall survival of mesothelioma patients, and five of these were also associated with relapse-free survival.
  • High expression of AUNIP, FANCI, LASP1, PSMD8 and XPO5 was associated with poor overall and relapse-free survival.
  • FANCI and LASP1 expression was positively correlated with infiltration by B cells, macrophages and dendritic cells. PSMD8 and XPO5 overexpression was associated with increased infiltration of B cells and dendritic cells.
  • Two immune subtypes (IS1 and IS2) were identified from 2,108 immune-related genes in the 86 TCGA samples. IS1 had a better prognosis than IS2 in the TCGA cohort.
  • No notable differences in tumor mutational burden or number of mutated genes were seen between IS1 and IS2.
  • Of 47 immune checkpoint genes, 10 (21.3%) were differentially expressed between subtypes in the TCGA cohort and 35 (74.5%) in the GEO cohort.
  • Immunogenic cell death genes: 4 of 22 (18.2%) in the TCGA cohort and 15 of 26 (57.7%) in the GEO cohort differed between IS1 and IS2.
  • IS2 showed rich immune cell infiltration and was characterized as immune "hot"; IS1 lacked immune cell infiltration and was characterized as immune "cold".
• The authors' conclusion: The authors concluded that AUNIP, FANCI, LASP1, PSMD8 and XPO5 are putative tumor antigens for mRNA vaccine development, and that patients with the IS1 subtype could be more suitable for mRNA vaccination.
• Limitations the authors state:
  • The findings need experimental verification, including mRNA vaccine synthesis and purification, and mouse models of mesothelioma.
  • The suggestion that the candidate antigens are processed by antigen-presenting cells and trigger an adaptive immune response is speculation that requires further research.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Immunotherapy, Prognosis.

Related studies

• Identification of Tumor Antigens and Immune Subtypes of Malignant Mesothelioma for mRNA Vaccine Development — S. Wang, Y. Yang, et al. (2022)
• Safety of mRNA-COVID-19 Vaccines in Patients With Thoracic Cancers — G. Spitaleri, P. Trillo Aliaga, et al. (2023)
• Potential of fluoropyrimidine to be an immunologically optimal partner of immune checkpoint inhibitors through inducing immunogenic cell death for thoracic malignancies — H. Kozai, H. Ogino, et al. (2024)
• Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies — G.L. Beatty, A.R. Haas, et al. (2014)
• Practical utility of insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1, and epithelial membrane antigen for distinguishing malignant mesotheliomas from benign mesothelial proliferations — S. Chang, M.H. Oh, et al. (2014)
• Human embryonal epithelial cells of the developing small intestinal crypts can express the Hodgkin-cell associated antigen Ki-1 (CD30) in spontaneous abortions during the first trimester of gestation — D. Tamiolakis, J. Venizelos, et al. (2005)

Browse more research in Frontiers in Cell and Developmental Biology, or return to medical research.