Identification of Tumor Antigens and Immune Subtypes of Malignant Mesothelioma for mRNA Vaccine Development

Our plain-English summary of Identification of Tumor Antigens and Immune Subtypes of Malignant Mesothelioma for mRNA Vaccine Development, by S. Wang, Y. Yang, L. Li, et al (Vaccines, 2022).

The study

• Authors: S. Wang, Y. Yang, L. Li, P. Ma, Y. Jiang, M. Ge, Y. Yu, H. Huang, Y. Fang, N. Jiang, H. Miao, H. Guo, L. Yan, Y. Ren, L. Sun, Y. Zha, N. Li
• Journal: Vaccines
• Published: 2022;10(8)
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: mRNA-based cancer vaccines have been considered a promising anticancer therapeutic approach against various cancers, yet their efficacy for malignant mesothelioma (MESO) is still not clear. The present study is designed to identify MESO antigens that have the potential for mRNA vaccine development, and to determine the immune subtypes for the selection of suitable patients.

Methods: A total of 87 MESO datasets were used for the retrieval of RNA sequencing and clinical data from The Cancer Genome Atlas (TCGA) databases. The possible antigens were identified by a survival and a genome analysis. The samples were divided into two immune subtypes by the application of a consensus clustering algorithm. The functional annotation was also carried out by using the DAVID program. Furthermore, the characterization of each immune subtype related to the immune microenvironment was integrated by an immunogenomic analysis. A protein-protein interaction network was established to categorize the hub genes.

Results: The five tumor antigens were identified in MESO. FAM134B, ALDH3A2, SAV1, and RORC were correlated with superior prognoses and the infiltration of antigen-presenting cells (APCs), while FN1 was associated with poor survival and the infiltration of APCs. Two immune subtypes were identified; TM2 exhibited significantly improved survival and was more likely to benefit from vaccination compared with TM1. TM1 was associated with a relatively quiet microenvironment, high tumor mutation burden, and enriched DNA damage repair pathways. The immune checkpoints and immunogenic cell death modulators were also differentially expressed between two subtypes. Finally, FN1 was identified to be the hub gene.

Conclusions: FAM134B, ALDH3A2, SAV1, RORC, and FN1 are considered as possible and effective mRNA anti-MESO antigens for the development of an mRNA vaccine, and TM2 patients are the most suitable for vaccination.

In plain English

This was a computer-based analysis of existing genetic data. No vaccine was made or tested. The authors used RNA-sequencing and clinical data for 87 malignant mesothelioma tumor samples from The Cancer Genome Atlas. They looked for genes that might serve as targets for a future mRNA vaccine and sorted the samples into immune subtypes. They identified five candidate genes. Higher expression of FAM134B, ALDH3A2, SAV1 and RORC was linked to longer overall survival, while FN1 was linked to poorer survival. In a multivariate analysis, FN1 (hazard ratio 1.22, p = 0.014) and RORC (hazard ratio 0.84, p = 0.006) were significantly associated with survival. The samples split into two immune subtypes, and TM2 was linked to better survival than TM1. Tumor mutation burden did not differ between the subtypes. FN1 was identified as a central "hub" gene. The authors concluded that the five genes are potential antigens for mRNA vaccine development and could be beneficial for TM2 patients. They noted that the study was retrospective and that its findings need validation. Asbestos exposure was not studied.

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: Retrospective bioinformatics analysis of public gene-expression, mutation and clinical data. No laboratory, animal or human vaccine testing was done.
• Who was studied: 87 malignant mesothelioma (MESO) tumor samples with RNA-sequencing and clinical data from The Cancer Genome Atlas (TCGA). The article does not say how many were pleural or peritoneal.
• Exposure: Not studied. The study analyzed tumor gene expression and mutations, not asbestos or other exposures. Asbestos is mentioned only as background in the introduction.
• Main results:
  • Five candidate tumor antigen genes were identified: FAM134B, ALDH3A2, SAV1, RORC and FN1.
  • Higher expression of FAM134B, ALDH3A2, RORC and SAV1 was related to better overall survival. FN1 was associated with poorer overall survival.
  • In multivariate Cox regression, two of the five genes were significantly associated with overall survival: FN1 (HR = 1.22, p = 0.014) and RORC (HR = 0.84, p = 0.006). No confidence intervals were reported.
  • The samples were grouped into two immune subtypes. TM1 was linked to worse survival and TM2 to better prognosis.
  • TM2 tumors had higher tumor purity and a significantly lower stromal score. Immune scores showed no obvious difference between the subtypes.
  • Tumor mutation burden did not differ between the two subtypes. The proportion of mutated genes was 87.5% in TM2 tumors and 75.86% in TM1 tumors.
  • 6 of 25 immunogenic cell death genes (24.0%) and 13 of 45 immune checkpoint genes (28.9%) were differentially expressed between the subtypes.
  • In a protein interaction network analysis, FN1 was identified as the hub gene.
• The authors' conclusion: The authors concluded that FAM134B, ALDH3A2, SAV1, RORC and FN1 are potential mesothelioma antigens for mRNA vaccine development and could be beneficial for TM2 patients. They also proposed FN1 as a potential biomarker.
• Limitations the authors state:
  • The study was retrospective.
  • The identified vaccine antigens and prognostic markers have not been validated. The authors call for further laboratory (in vitro) and animal (in vivo) studies.

Topics

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

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