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

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.

Using the Collaborative Cross and Diversity Outbred Mice in Immunology

“…In this paper, the authors describe the creation of the model by crossing the CC lines with the MexTAg transgenic mouse, which develops mesothelioma upon asbestos exposure (Robinson et al., 2006). With this model, the authors aim to utilize genetic mapping and “omics” data to understand modifier genes influencing immune response to asbestos‐induced mesothelioma (Behrouzfar et al., 2021).…”

The MexTAg collaborative cross: host genetics affects asbestos related disease latency, but has little influence once tumours develop

“…To address these challenges, we developed a unique mouse model, the MexTAg Collaborative Cross (CCMT) ( Behrouzfar et al, 2021 ). We combined the genetically diverse Collaborative Cross (CC), with the well-characterised MexTAg mesothelioma mouse model ( Robinson et al, 2006 ; Robinson et al, 2011 ).…”

Variant Enrichment Analysis to Explore Pathways Disruption in a Necropsy Series of Asbestos-Exposed Shipyard Workers

“…Despite using separate and well-characterized cohorts of controls and mesothelioma patients, a number of GWAS studies failed to identify common genetic risk factors associated with mesothelioma [ 19 , 24 , 25 , 27 ]. Germline mutations in BRCA1-associated protein 1 (BAP1) and some DNA repair genes have been considered as predisposing genetic factors associated with mesothelioma development [ 11 , 25 , 28 , 29 ].…”