Renal cell carcinoma (RCC) can lead to significant morbidity and mortality in our patients. Despite the fact that approved therapies, such as pazopanib and sunitinib, which target the vascular endothelial growth factor (VEGF) pathway, and immune-targeted therapies help patients with metastatic RCC, we still see patients develop disease progression. Agents that target VEGF can slow disease progression in a significant number of patients. However, only about one-third of patients who receive these agents respond to treatment. Moreover, the majority of patients develop resistance within about one year. Recently, new advances such as the approval of immune checkpoint inhibitors have come into use. And although the results are generally favorable when patients respond to this type of therapy, only one-quarter of all patients respond, and those that do respond have a limited duration of effect. As a result, there is an urgent need to find novel treatment options for patients with RCC. Our lab has identified a molecule that plays a key role in the regulation of the immune response to cancer. This molecule, HHLA2, is expressed in low levels on normal cells but is found to be highly expressed on cancer cells. T cells are cells in the body that have the ability to destroy harmful cells (i.e., cancer cells); however, it is not known whether HHLA2 inhibits or activates T cells. We believe that HHLA2 plays a key role in regulating T-cell function and that, as a result, HHLA2 may serve as a novel therapeutic target in the treatment of RCC. We will begin to investigate the role of HHLA2 by creating humanized mice or human xenograft models of RCC. Our lab has already created cell lines that express high levels of HHLA2; with these tools we will be able to assess this molecule's function by using a panel of antibodies to block its function. We will use several different cell lines, from human renal cell cancers, to rigorously test our hypothesis. We are very optimistic that the results of our studies will provide enough rationale to justify clinical trials in the near future. If, by the end of our grant, we are successful in achieving the goals of this research, we hope to learn (1) whether HHLA2 inhibits or activates the immune system; (2) whether any antibodies at our disposal block HHLA2's function; and, finally, (3) how HHLA2 functions in an organism as examined through our mouse models.