Optimizing Active Immunotherapy of Melanoma Through Metabolic Reprogramming of Melanoma Antigen-Specific CD8plus T Cells Combined with Checkpoint Blockade
Abstract
The grant focuses on testing the hypothesis is that the success rate of active immunotherapy of advanced melanoma based on vaccines or adoptive transfer of MAA-specific T cells can be optimized by metabolic reprogramming of T cells from glycolytic energy production towards the use of fatty acid oxidation. As we published, the interstitial fluids of melanomas have low glucose (Glc) contents while free fatty acid (FA) species increase during tumor progression. CD8plus T cells upon activation in the periphery switch to glycolytic energy production. Once CD8plus T cells enter the Glc-depleted environment of melanomas, starvation drives their differentiation towards functional exhaustion and apoptosis, unless they switch towards the use of alternative nutrients, such as FAs, for energy and biomass production. Metabolism can be modified by drugs, such as fenofibrate (FF), an agonist of PPAR-a. This in turn improves tumor infiltrating lymphocyte (TIL) functions, which results in more sustained tumor regression. CD8plus TIL performance can be further enhanced by complementing metabolic reprogramming with a PD-1 checkpoint inhibitor, which in melanoma renders PD- L1plus tumors cells more susceptible to cytolysis. These hypotheses are supported by our data.22 Most of these studies were thus far conducted in mice using adoptive transfer models. Prior to clinical trials, the relevance of our findings for human tumors has to be confirmed using approaches that are suitable for use in melanoma patients.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1191163
Entities
People
- Hildegund C.j. Ertl
Organizations
- Wistar Institute