Sequencing of normal tissues has now established that aging cells in the blood, skin, liver, bladder, and esophagus accumulate a high abundance of somatic mutations prior to cancer. While our work on somatic mutations in the liver supports the possibility that some mutations are beneficial, the development of cancer is generally correlated with increased mutation burden. Immunosurveillance is clearly important for the suppression of tumor initiation and progression, but it is unknown if it exerts selective pressure on mutant clones prior to tumor initiation. Furthermore, if immune hyperactivation is able to selectively cull mutant clones destined for cancer, then it is possible that cancer r...

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Sequencing of normal tissues has now established that aging cells in the blood, skin, liver, bladder, and esophagus accumulate a high abundance of somatic mutations prior to cancer. While our work on somatic mutations in the liver supports the possibility that some mutations are beneficial, the development of cancer is generally correlated with increased mutation burden. Immunosurveillance is clearly important for the suppression of tumor initiation and progression, but it is unknown if it exerts selective pressure on mutant clones prior to tumor initiation. Furthermore, if immune hyperactivation is able to selectively cull mutant clones destined for cancer, then it is possible that cancer risk could be dramatically reduced using immune checkpoint inhibitor treatments. We hypothesize that the adaptive immune system is the most important non-autonomous effector of clonal selection in normal tissues, and increasing or decreasing immune function will preferentially select for or against certain mutant pathways, leading to major influences on cancer evolution. While these are questions with far reaching implications, there have not been tractable and high-fidelity animal models in which somatic mutations in normal tissues can be followed. To experimentally generate and track somatic mutations in a systematic fashion, we have developed genetically mosaic mice using CRISPR gene editing. To test the role of the immune system on the normal tissue mutation landscape, we will perform somatic mutation analysis in immunocompetent, immunodeficient, and immune checkpoint inhibitor treated mice. We will then determine if immune checkpoint inhibition can prevent tumorigenesis associated with somatic mutagenesis during aging. These experiments will test the hypothesis that the immune system limits cancer risk by pruning pre-malignant mutated cells rather than just established cancer cells and establish the mechanistic basis for exploiting immunotherapy in cancer prevention.

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