Immunometabolomics · CD8+ T cell metabolism in anti-tumor response
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2017-07-01 → 2020-06-30
- EU contribution
- €257,191
- Participants
- 2
- Scheme
- MSCA-IF-GF
Lines connect the coordinator with its partners.
Results in brief
CD8+ T cell metabolism in anti-tumor response
Cancer immunotherapy is a therapy based on the modulation of the immune system response, mainly through the stimulation of the immune cells that have the natural ability to fight cancer, to help the body fight cancer. Cytotoxic T cells (also known as CD8+ T cells) play a central role in cell-mediated immunity and are the main target of some immunotherapy-based therapies that are currently applied in cancer. The main objective of the project “Immunometabolomics: CD8+ T cell metabolism in anti-tumor response” is to understand some aspects of CD8+ T cell metabolism that are yet unknown. We have focused on the study of one-carbon (1C) metabolism and NADPH metabolism. 1C metabolism, mediated by the folate co-factor, supports multiple physiological processes including biosynthetic pathways (e.g. purines and thymidine), amino acid homeostasis (e.g. glycine, serine, and methionine), epigenetic maintenance (through methyl group transfer reaction) and can also contribute to the reduction of NADPH. NADPH is a cofactor that can accept electrons to be further utilized by the cells for biosynthesis (e.g. proline, fatty acids, deoxynucleotides…) and for scavenging reactive oxygen species (i.e. mainly through the intracellular metabolite glutathione). We aimed to understand basic aspects of metabolism in CD8+ T cells, and how nutrient-deprived conditions in the tumor microenvironment shape CD8+ T cell metabolism and function, to see if it is possible to identify pharmacological or nutritional interventions that could synergize with existing checkpoint inhibitors for immunotherapy through the modulation of 1C and NADPH metabolism. To this end, we have combined nutrient and pharmacological manipulations in vitro and in vivo, using mass spectrometry and isotope tracers to read out pathway activity and cell surface markers and released/intracellular cytokines to read out immune cell functional status.
Data: CORDIS, © European Union
Project objective
Although cancer immunotherapy has achieved significant breakthroughs in recent years that has positioned it as the most promising approach to treat cancer, its overall efficacy remains limited in the majority of patients. Nutrition-deprived conditions at tumor microenvironment poses significant metabolic challenges to tumor-infiltrating lymphocytes which may contribute to failure of anti-tumor activity. The main objective of the Immunometabolomics project is to understand metabolism in CD8+ T cells, during active effector T cell development and exhaustion, using approaches that go beyond current research which have been mostly focused on glucose/energy metabolism thus disregarding the relevance of anabolic and redox reactions that are crucial in correct cellular function and proliferation. Open-ended metabolomics and metabolic flux analysis studies, in combination with genetic, nutrition and pharmacological manipulations will be employed to study areas of metabolism that have not been previously extensively studied in CD8+ T cells including 1C metabolism. The characterization of metabolism in CD8+ T cells will be gradually performed in models of higher complexity and physiological and clinical relevance from in vitro, to in vivo in genetically engineered mouse models of lung cancer and finally in lung cancer patients. Through understanding CD8+ T cell metabolism, and its modulation in cancer within tumor microenvironment, we aim to develop a basic science foundation for increasing immunotherapy efficiency in cancer through the use of complementary nutritional and/or metabolism-targeted pharmacological approaches.
Original text from CORDIS.
Participants
- FUNDACION PARA LA INVESTIGACION DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA · ValenciaCoordinatorSpain
- TRUSTEES OF PRINCETON UNIVERSITY · Princeton, NjUnited States
Links
Data: CORDIS, © European Union