Optimizing Active Immunotherapy of Melanoma Through Metabolic Reprogramming of Melanoma Antigen Specific CD8+ T Cells Combined withCheckpoint Blockade
Abstract
The grant focuses on testing the hypothesis is that the success rate of active immunotherapy of advanced melanoma based onvaccines or adoptive transfer of MAA-specific T cells can be optimized by metabolic reprogramming of T cells from glycolytic energyproduction towards the use of fatty acid oxidation. As we published, the interstitial fluids of melanomas have low glucose (Glc) contentswhile free fatty acid (FA) species increase during tumor progression. CD8 T cells upon activation in the periphery switch to glycolyticenergy production. Once CD8 T cells enter the Glc-depleted environment of melanomas, starvation drives their differentiation towardsfunctional exhaustion and apoptosis, unless they switch towards the use of alternative nutrients, such as FAs, for energy and biomassproduction. Metabolism can be modified by drugs, such as fenofibrate (FF), an agonist of PPAR-. This in turn improves tumor infiltratinglymphocyte (TIL) functions, which results in more sustained tumor regression. CD8 TIL performance can be further enhanced bycomplementing metabolic reprogramming with a PD-1 checkpoint inhibitor, which in melanoma renders PD- L1 tumors cells moresusceptible to cytolysis. These hypotheses are supported by our data.22 Most of these studies were thus far conducted in mice using adoptivetransfer models. Prior to clinical trials, the relevance of our findings for human tumors has to be confirmed using approaches that aresuitable for use in melanoma patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2021
- Accession Number
- AD1143205
Entities
People
- Hildegund C. Ertl
Organizations
- Wistar Institute