The “abscopal effect” suggests that the use of ionizing radiation to treat primary tumors has a secondary clinical benefit of sensitizing metastatic tumors to an activated immune response. However, RCC is notoriously resistant to radiation therapy. Dr. Pal has previously demonstrated that targeted delivery of the chemotherapeutics, everolimus and YM155 (EY-L), inhibits tumor growth in mice, and separately sensitizes kidney cancer cells to radiation in the laboratory. With the mentorship of Dr. Debabrata Mukhopadhyay (Mayo Clinic and Foundation, Jacksonville), Dr. Pal proposes to evaluate how combining EY-L with radiation might act synergistically to treat primary RCC in several mouse models. Initially, studies will be performed in mice lacking an immune response to determine if EY-L can sensitize RCC xenografts to radiation in the body. These studies will then be extended by introducing a syngeneic mouse RCC tumor model to mice with a functioning immune system to begin to explore how EY-L and radiation of the primary tumor may also function to induce an abscopal effect, reducing or eliminating detectable metastatic lesions by activation of the immune system. Finally, Dr. Pal will explore these therapeutic modalities in the presence of Interleukin-2 (IL-2) treatment, which has been shown to promote an immune-response in the tumor microenvironment, potentially boosting the effectiveness of treatment at both the primary tumor, and metastatic lesions via enhanced abscopal effect. If successful, these results would provide preclinical evidence that RCC can be sensitized to radiotherapy with an added benefit of metastatic reduction, affording additional frontline treatment options that could be translated into early clinical trials.