The success of checkpoint inhibitors for treating metastatic cutaneous melanoma and other cancers has generated interest in immunologic therapies; however, only a subset of cancers responds to such therapies, whereas many cancers are unresponsive. While low tumor mutation burden may explain in part why cancer types are immunologically “cold,” recent discoveries suggest that active immune suppression by the tumor plays an important role. It is unclear in most cases how cancer cells create such an inhibitory immune microenvironment. Elucidating the mechanisms of this immunosuppression could generate novel therapies. One cancer ...

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The success of checkpoint inhibitors for treating metastatic cutaneous melanoma and other cancers has generated interest in immunologic therapies; however, only a subset of cancers responds to such therapies, whereas many cancers are unresponsive. While low tumor mutation burden may explain in part why cancer types are immunologically “cold,” recent discoveries suggest that active immune suppression by the tumor plays an important role. It is unclear in most cases how cancer cells create such an inhibitory immune microenvironment. Elucidating the mechanisms of this immunosuppression could generate novel therapies. One cancer type that is poorly responsive to checkpoint inhibitors is uveal melanoma (UVM), which is a highly metastatic eye cancer with poor prognosis and low survival. In UVM, evidence suggests that the main genetic drivers of metastasis – inactivation of BAP1 and misexpression of PRAME – cause an immunosuppressive state through induction of chromosomal instability. We will use complementary methods to determine how BAP1 loss and PRAME misexpression cause chromosome instability and how chromosomal instability drives formation of an immunosuppressive tumor microenvironment. We will take advantage of resources we have generated, including genetically engineered UVM and uveal melanocyte (UMC) cell lines, a novel orthotopic syngeneic mouse model of UVM, and a large biobank of human tumor samples for validation of key findings. UT Southwestern is the ideal place to conduct this work, as many experts that we want to collaborate with are on the faculty there, including Drs. Peter Ly, James Brugarolis, Zhijian Chen, and Joshua Mendell. Additionally, core facilities at UT Southwestern are ideally suited to support the proposed research. Our objective is to identify promising new targets that can be translated into clinical trials for patients with UVM and other cancer types.

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