The long-term objective of this project is to elucidate the role of cancer-related aneuploidy (i.e. the presence of an abnormal karyotype) during tumorigenesis and, specifically, in cancer immune evasion. Aneuploidy is a hallmark of human solid tumors and mounting evidence, both from mouse models and human cancers, suggests that aneuploidy represents a driver event during tumorigenesis. Despite this evidence, the role of aneuploidy in cancer is not well understood. We performed a bioinformatic analysis comparing the transcriptomes of primary tumor samples containing high versus low levels of aneuploidy. Tumors with high aneuploidy displayed a strong decrease in the degree of tumor-infiltrating immune cells, including markers of CD8+ T cells, NK cells, and B cells. Based on this analysis and other data, we hypothesize that cancer- associated aneuploidy contributes to tumorigenesis by promoting cancer immune evasion. The proposed research project will examine the role of aneuploidy in the regulation of tumor immune infiltrate and in cancer immune escape. Specifically, we will first investigate the effects of aneuploidy on antigen processing/presentation and on promoting resistance to CD8+ T cells-mediated cytotoxic activities. Secondly, we will study the effect of aneuploidy on tumor immune escape, by utilizing syngeneic tumor mouse models. Two mentors with complementary research skills will supervise the mentored phase of this proposal: Dr. Stephen Elledge, an expert in genetics and functional genomics, and Dr. Kai Wucherpfennig, an expert in cancer immunology and T cell biology. Their guidance will be imperative to the success of this project and to propel me into an independent research career. The proposed research has the potential (i) to improve our ability to predict the likelihood of a patient response to current immunotherapies for better, rational decision- making about treatment options; and (ii) to understand the molecular mechanisms underlying cancer immune evasion to improve current strategies and envision new potential therapeutic opportunities.
Cancer immunotherapy represents the most promising strategy of cancer treatment, however, the success rate is still limited to only a fraction of the patients. The purpose of this project is to explore and identify novel mechanisms of cancer immune evasion, thus promoting more effective immunotherapy approaches.