Saturday, November 23, 2024
11/23/2024
Adoptive T cell therapy for cancer has proven remarkably successful and is capable of producing high response rates and dramatic remission in some patients. Currently it is more effective against liquid than solid tumors, due to the environment within tumors being hostile for T cell survival and function. As is true of many tumors, melanomas are highly glycolytic, and deplete the local glucose concentration. Melanomas that develop resistance to Vemurafenib undergo metabolic remodeling to become dependent upon glutamine. As both glucose and glutamine are essential for effector CD8 T cell differentiation and anti-tumor effector functions, the T cell response is compromised in the tumor microenvironment. Advances in adoptive T cell therapy have focused mostly on better targeting and activation of tumor-specific T cells, however they may still fail to thrive in this metabolically challenging environment. Engineering cells with the flexibility to use multiple carbon sources, with less reliance on glucose and glutamine, is one very promising approach that could be layered onto any tumor targeting strategy. In this application we show that CD8 T cells lacking in the transcriptional repressor Zbtb20 display enhanced glycolytic and mitochondrial metabolism, and increased fuel flexibility relative to wild- type cells. Single cell transcriptional profiling confirmed these metabolic changes and confirmed phenotypic studies showing a skewing toward the memory fate. Consistent with these attributes being favorable for anti- tumor immunity, we found adoptive transfer of Zbtb20-deficient CD8 T cells conferred superior immunity upon challenge with melanoma or adenocarcinoma cells. Therefore, suppression of Zbtb20 is a very promising approach to improve T cell metabolism for adoptive immunotherapy. In this proposal we determine the precise molecular mechanisms underlying enhanced anti-tumor immunity, mechanisms for elevated glycolytic and mitochondrial metabolism, and the extent to which each change is responsible for anti-tumor immunity. We also determine the extent to which a dominant negative mutant of Zbtb20 can replicate enhanced protection observed in Zbtb20 deficient cells, as this is more readily translatable to human T cells. These studies will reveal the mechanism(s) by which Zbtb20 deficiency enhances anti-tumor immunity and investigates strategies that can be translated into human T cell adoptive therapy.
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