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.

Keywords: Collaborative Cross; MexTAg; host genetics; mesothelioma; thoracic malignancies; tumor immune microenvironment.

Figure 1

A schematic of the CC‐MexTAg experimental design. The generation of CC‐MexTAg mice and their exposure to asbestos (Study 1): Briefly, candidate modifier genes will be mapped with mesothelioma‐free survival, as a quantitative trait using the GeneMiner Bioinformatics pipeline. Genome wide scans will be used to define chromosomal locations of peak single nucleotide polymorphism (SNPs) associated with each of the characterized mesothelioma phenotypes, such as disease progression, latency, overall survival, and mesothelioma incidence. Gene expression analysis and immunofluorescence analysis of tumors collected from CC‐MexTAg mice exposed to asbestos (Study 2): Comprehensive analyses of gene expression profiles and immune cell infiltrate of the tumor microenvironment will be performed to identify any differences between distinct CC‐MexTAg groups. These data will be correlated back to phenotypic data from Study 1, to build a broader understanding of the impact of host genetics on asbestos related disease development.