Vivek Verma, PhD, CRI CLIP Investigator University of Minnesota Area of Research: Melanoma To enhance mitochondrial fitness and prevent T cell exhaustion, Dr. Verma intends to explore the possibility of targeting pyruvate kinase (PK)M2, an enzyme involved intricately in regulating metabolism and gene expression in CD8 T cells. Through this research, Dr. Verma anticipates developing a clinically relevant target that can be utilized for enhancing metabolic fitness, preventing immune cell exhaustion, and reversing resistance to immune therapy. Melanoma is one of the most aggressive and deadly skin cancers. Immunotherapy using immune checkpoint blocking (ICB) antibodies such as anti-PD1 and anti-CTLA4 is a promising therapeutic strategy for patients with advanced melanoma. However, even in the optimal scenarios with combination ICB therapy, approximately half of patients do not respond to the therapy. Activating immune cells is a critical factor that decides therapeutic outcomes. Mitochondria are an integral part of cellular energy machinery that play significant roles in the activation, proliferation, differentiation, and effector functions of immune cells. Impaired mitochondrial functions are associated with diminished activation and increased exhaustion in T cells. Tumor-infiltrating lymphocytes (TILs) show repressed mitochondrial metabolism and decreased mitochondrial mass that renders TILs exhausted and ineffective in curing cancer. Organization of mitochondrial inner membrane structures called cristae seem to be extremely important for mitochondria to optimally function. Projects and Grants Targeting T cell exhaustion via mitochondrial reorganization for enhanced immunotherapy of melanoma University of Minnesota | Melanoma | 2023
