How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers

Our plain-English summary of How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers, by K. Behrouzfar, K. Burton, S.E. Mutsaers, et al (Frontiers in Oncology, 2021).

The study

• Authors: K. Behrouzfar, K. Burton, S.E. Mutsaers, G. Morahan, R.A. Lake, S.A. Fisher
• Journal: Frontiers in Oncology
• Published: 2021;11:679609
• Type of article: Review
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC-MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.

Copyright © 2021 Behrouzfar, Burton, Mutsaers, Morahan, Lake and Fisher.

In plain English

This article is a review by researchers at the National Centre for Asbestos Related Diseases in Western Australia. The authors discussed published research on how inherited (host) genes may affect thoracic cancers and the immune response to them. These cancers include lung cancer, malignant mesothelioma and thymic epithelial tumors. They wrote that genome-wide association studies have found inherited risk factors for lung cancer. They also wrote that numerous such studies have failed to find common genetic risk factors broadly associated with mesothelioma, partly because few patients are available to study. The authors then described their own mouse model, CC-MexTAg. It crosses genetically varied Collaborative Cross mouse strains with MexTAg mice, which develop mesothelioma after asbestos exposure. Over 2500 of these mice, from 72 strains, had been exposed to asbestos and followed for up to 18 months. Preliminary data from 55 groups that had finished observation showed greater than 3-fold variation in median overall survival. The parental MexTAg mice survive 365 days. The authors concluded that the model will give a detailed picture of genes and pathways linked to the immune response in mesothelioma. The article did not name the asbestos fiber type.

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: Review, which also briefly reports preliminary data from the authors' own ongoing mouse experiment (CC-MexTAg)
• Who was studied: Reviewed literature on lung cancer, malignant mesothelioma and thymic epithelial tumors. The authors' own data come from over 2500 CC-MexTAg mice bred from 72 Collaborative Cross strains crossed with MexTAg mice.
• Exposure: Asbestos (fiber type and dose not stated). The mice were exposed and then monitored for up to 18 months or until asbestos-related disease reached a defined endpoint.
• Main results:
  • Preliminary data from the CC-MexTAg groups that had completed the observation period (55 groups) showed greater than 3-fold variation in median overall survival.
  • For comparison, the authors stated that the parental MexTAg mice survive 365 days.
  • From the reviewed literature: numerous genome-wide association studies have failed to identify common genetic risk factors broadly associated with mesothelioma.
  • From earlier work described in the review: MexTAg mice develop mesothelioma with pathology similar to humans, but only after asbestos exposure.
• The authors' conclusion: The authors concluded that the CC-MexTAg mouse model, especially combined with tumor gene expression data, will provide a detailed picture of modifier genes and biological pathways associated with the immune response in mesothelioma.
• Limitations the authors state:
  • The authors described their own mouse data as preliminary. Some groups had not yet completed observation, and complete data were expected by late 2021.

Topics

Medical terms in this study, explained in our Lexicon: Lung Cancer, Malignant Mesothelioma, Mesothelioma, Tumor Microenvironment.

Related studies

• The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop — S.A. Fisher, K. Patrick, et al. (2024)
• The Influence of Genetic Variability on the Risk of Developing Malignant Mesothelioma — A. Franko, N. Kotnik, et al. (2018)
• Combination immune checkpoint blockade as an effective therapy for mesothelioma — V.S. Fear, C. Tilsed, et al. (2018)
• PD-L1 Testing for Immune Checkpoint Inhibitors in Mesothelioma: For Want of Anything Better? — S. Lantuejoul, N. Le Stang, et al. (2017)
• In response to Sharing different perspectives to understand asbestos-induced carcinogenesis: A comment to Jiang et al. (2016) by Alessandro Francesco Gualtieri (2017) — S. Toyokuni, L. Jiang (2017)
• Mesothelioma developing in carriers of inherited genetic mutations — Y. Yoshikawa, M. Emi, et al. (2020)

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