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.
Highlights
Thoracic cancers including lung cancer (LC), malignant mesothelioma and thymic epithelial tumors (TETs) are among the most lethal cancers [1]
While advances have been made in our understanding of how genetic alternations impact cancer development and treatment outcomes for common thoracic malignancies like lung cancer, our knowledge remains limited for less common cancers such as mesothelioma and TETs
Understanding how the host immune system interacts with a developing tumor is essential for the rational development of new or improved treatment regimens for thoracic malignancies
Summary
Thoracic cancers including lung cancer (LC), malignant mesothelioma and thymic epithelial tumors (TETs) are among the most lethal cancers [1]. Immunotherapies have improved treatment outcomes for some thoracic cancers, success is often limited to a subset of patients, while prognosis for the majority of patients remains dismal [5] This dichotomy in response, highlights the need to better understand interactions between thoracic cancer cells and the host immune system that underpin an effective response to cancer immunotherapy. Advances in high-throughput sequencing technologies and associated computational analysis pipelines allow us to investigate the interplay between tumor cells and the immune microenvironment [6, 7] These technologies enable us to broaden our knowledge of the immunobiology of tumor-host interactions by identifying immune-related genetic alterations associated with cancer development [6, 7]. We propose our unique murine model; the MexTAg Collaborative Cross (CC−MexTAg), as a strategy to overcome current limitations of conventional genetic studies in mesothelioma, to improve our knowledge about the impact of host genetics on initiating immune responses and the developing tumor microenvironment
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