The team led by Bruno Silva Santos, Principal Investigator and Deputy Director of the Instituto de Medicina Molecular João Lobo Antunes (iMM) and Professor at the Faculdade de Medicina da Universidade de Lisboa, discovered that the functions of a subtype of white blood cells – gamma delta T cells – are regulated by metabolic resources, namely sugars and fat. The results now published in the scientific journal Nature Immunology*, open new avenues for the use of sugar metabolism in gamma-delta T cells as an effective tool in cellular immunotherapy of cancer, in addition to building further on the concept that high cholesterol levels are a barrier to its effectiveness.
Gamma-delta T cells are a subgroup of white blood cells that have the ability to effectively eliminate tumor cells. Bruno Silva Santos’s research group has been studying the biology of these cells for several years, and has also developed protocols for its use in cancer cell immunotherapy (scheduled to be implemented in clinical trials later this year). Now, in a preclinical study, the researchers have shown that the anti-tumor functions of gamma-delta T cells, which lead to the elimination of tumor cells, depend on consumption and metabolization of glucose (a simple sugar). “Our results indicate that supplementation of the lymphocytes with high glucose levels substantially increases their ability to inhibit tumor growth upon transfer to an experimental model of breast cancer”, explains Noella Lopes, first author of the scientific paper. On the contrary, the results show that supplementation of gamma-delta T cells with cholesterol, a type of fat, promotes pro-tumor functions, that is, molecules that help the breast tumors to grow. The same happened in a melanoma model, as a result of feeding the animals a diet rich in cholesterol. The researchers also showed that this dichotomy in the use of energy resources (sugars versus fats) is found already in the thymus, the organ where T lymphocytes are generated, and is maintained in the various tissues of the body and in tumors, including the models of breast and colorectal cancers studied by the iMM team. “These results open new perspectives for research in immunotherapy based on metabolic principles, aiming at a more effective stimulation of anti-tumor gamma delta T-lymphocytes. On the other hand, a deeper understanding of the harmful effects of cholesterol on tumor progression raises important questions about the effect of diet on cancer immunotherapy”, concludes Bruno Silva Santos.
This study was the result of a collaboration between the iMM researchers and colleagues from Harvard Medical School (USA) and Queen Mary University of London (United Kingdom), and was funded by various international funding bodies including the European Research Council (ERC), the National Institutes of Health (USA) and the Wellcome Trust (UK).
*Lopes N*, McIntyre C*, Martin S*, Raverdeau M*, Sumaria N, Kohlgruber A, Fiala G, Dyck L, Kellis M, Brenner M, Argüello RJ, Silva-Santos B**, Pennington DJ** and Lynch L** (2020). Distinct metabolic programs established in the thymus control the effector functions of γδ T cell subsets in tumour microenvironments. Nature Immunology: in press (* & ** Equal contributions)