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The Role of MHC Variation in Tumor Progression


Tumors arise when cells accumulate genomic alterations that allow them to sustain rapid growth. Since the immune system is capable of eliminating tumor cells, another prerequisite for tumor formation is evasion of immune recognition. Recently, therapies that reactivate the immune system have been able to eliminate some tumors. However, only a small fraction of patients receives a sustained benefit from these immunotherapies, suggesting that we have yet to understand the complexity of tumor-immune interactions. The immune response to tumors is mediated by the major histocompatibility complex (MHC), one of the most variable molecules encoded by the human genome. The MHC communicates cellular health to the immune system by binding and presenting antigen to circulating T cells. Due to technical limitations, the impact of the inter-patient MHC heterogeneity on tumor development has remained understudied. To address this gap, I utilized a large phenotypically-annotated cohort of cancer patient and recent algorithmic advances to assess the role of MHC variation on tumor progression. Though there are two classes of MHC with different functional mechanisms, I found that germline variation in both classes impacts patient mutation susceptibility and population mutation frequencies. Furthermore, the influence of MHC variation on tumor progression varies with the sex and age of the patient. The methods I developed expose the role of the immune system in shaping tumor formation and lay the foundation for improved development of immunotherapies.

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