Mechanisms of liver metastasis and associated resistance to immunotherapy

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PROJECT SUMMARY The incidence of melanoma has doubled in the last three decades and is projected to exceed 100,000 cases in the US in 2020. Almost 7,000 people died of melanoma in the US in 2019. Melanoma has a strong propensity to spread both via lymphatic and hematogenous routes. The most common sites of metastasis include lymph nodes, lung, liver and brain. Although novel therapies, such as immunotherapies have improved survival of patients with metastatic disease, metastatic patterns can influence responses to such therapies. In particular, patients with metastases to the liver have a lower response and survival rates in response to immune checkpoint inhibitors compared to patients with metastases to other organs. The molecular underpinnings of liver metastasis development and the impact on drug response and resistance are poorly understood. This is in part due to limited pre-clinical models that resembles metastatic patterns seen in patients, and a sparsity of genomic characterization of human liver metastatic lesions. The goal of this proposal is to determine drivers of melanoma liver metastasis (MLM) and mechanisms of associated resistance to immunotherapies. For this purpose, we characterized and used a novel syngeneic mouse model that faithfully recapitulates genomic, metastatic and response patterns seen in patients. We performed a large-scale in vivo CRISPR-Cas9 screen and identified perturbations that promote development of MLM, but not primary tumor growth or metastasis to other organ sites. In the first aim of this proposal, we elucidate the cell intrinsic signaling mechanisms promoting MLM. Next, using integrated high-plex imaging, immune-profiling and single-cell sequencing, we determine the immune infiltrates of MLM and concurrent lung metastases and how the immune compartment impacts the response to clinically used immunotherapies. Finally, we assembled a large cohort of patient biopsies from liver metastases and concurrent metastases from other organ sites as well as peripheral blood mononuclear cells (PBMCs) for genomic and immune profiling. Together, these studies will provide a landscape of genomic determinants, signaling mechanisms and immune environments of MLM and their impact on responses to immunotherapies and have the potential to identify novel avenues for rationale drug development.