Defining the role of aberrant signal pathway activation in melanoma on the immune microenvironment

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PROJECT ABSTRACT Melanoma is a deadly malignancy of increasing incidence, with approximately 90,000 deaths estimated in 2018. Although recent advances in pathway targeted therapy (PTT) and immune therapy have revolutionized the treatment landscape of metastatic disease, these therapies are limited by acquired resistance and low response rates. Therefore, there is an urgent need to optimize treatment regimens, particularly in combination therapies in order to utilize the rapid response benefits of PTT and the durability of immunotherapy. Because clinical trials are limited by patient enrollment, there is a heavy reliance on preclinical models to provide translatable justification of treatment regimens. Unfortunately, the high rates of clinical trial failures have been historically attributed to the lack of preclinical models that efficiently recapitulate human disease, both in genetics and immune response. Thus this study seeks to establish an immunocompetent mouse model in which congenic mouse cell lines with defined melanoma genetic alterations can be transplanted into C57BL/6 mouse hosts. This will allow for the study of tumor immunity and immunotherapy response in an immunocompetent host using melanomas that accurately reflect the genetics of human melanoma. Aberrations in the RAS and CDKN2A signaling pathways are universally present in melanoma. PTT of BRAF, the most common mutation in melanoma and a downstream target of RAS, has been previously been shown to upregulate tumor immunity. In addition, downstream tumor suppressor pathways of CDKN2A have also been shown to enhance tumor immunity, although the direct role of CDKN2A on the tumor immune and immunotherapy response is not clear. Thus, a major goal of this study is to determine whether loss of CDKN2A contributes to immune evasion and immunotherapy resistance. Successful completion of these aims will not only provide biological insight into the role of aberrant signaling in melanoma on the tumor immune environment, but also better inform treatment regimens that can improve patient survival.