Targeting Elongation Factor-2 Kinase to Reinforce Melanoma Immunotherapy

The objective of this project is to understand the role and importance of eukaryotic elongation factor-2 kinase (eEF-2K), a unique enzyme that regulates protein synthesis and is highly expressed in several types of neoplasm including melanoma, in regulation of anti-tumor immunity, and to determine the impact of this kinase in immunotherapy for melanoma. As melanoma cells mostly express tumor-specific neo-antigens (Ags), immunotherapy such as adoptive cell transfer-based therapy (ACT) is considered a promising treatment for this notorious disease. Nevertheless, due to various factors that may weaken therapeutic immunity, the clinical outcome and benefit of this therapy remain less satisfactory. Accumulating evidence suggest that metabolic status of both immune cells and tumor cells has significant impact on the potency of ACT, and metabolic reprogramming may represent a viable target for reinforcing immunotherapy. We have revealed a critical role for eEF-2K in promoting aerobic glycolysis (Warburg effect) and the underlying mechanism. More recently, our preliminary studies showed that eEF-2K is critically required for the survival of certain suppressive immune cells. As metabolic reprogramming such as aerobic glycolysis plays crucial roles in regulating immune response and tumor sensitivity to therapeutic intervention, based on our intriguing preliminary results we hypothesize that eEF-2K-mediated metabolic reprogramming suppresses antitumor immunity; targeting eEF-2K would hasten death or reduce resilience of both tumor and suppressor immune cells and up-regulate expression of tumor Ags and related proteins, thereby relieving immune-suppression and reinforcing the efficacy of ACT against melanoma. To test this hypothesis, the current application proposes the following highly related and interactive specific aims: (1) To determine the role of tumoral eEF-2K in melanoma response to ACT; (2) To determine the impact of targeting eEF-2K in ACT against melanoma. We have already established the mouse and human PSC-derived antigen-specific CD8+ T lymphocytes, and the murine syngeneic melanoma model and humanized (NOD-scid IL2rgnull) mouse melanoma model for the proposed studies, and are well poised to accomplish the above aims. Completion of these studies may not only reveal eEF-2K as a unique molecular determinant of anti-tumor immunity, shed new light on the importance of eEF-2K in cancer, but also uncover novel therapeutic opportunities to improve ACT for melanoma through the eEF-2K-targeted strategy.