Metabolic enhancement of the anti-tumour immune response

• Applicant: Dr. Peter Kreuzaler
• Subject Area: Cell Biology ; Endocrinology, Diabetology, Metabolism ; Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558867709

B-class vitamins play a critical role in metabolic processes. As cofactors they support a plethora of metabolic reactions, spanning major pathways such as the Krebs cycle, pentose phosphate pathway, fatty acid biosynthesis, and the methionine cycle. We have been able to show that one B-class vitamin, Vitamin B5, is important both for cancer cells to sustain growth, as well as for cytotoxic T cells to fully activate after antigen recognition. Increased uptake of this vitamin is in both cases achieved by the increased expression of its cognate transporter SLC5A6. Immunotherapy, in other words the reactivation of the body’s own immune system, is one of the biggest recent breakthroughs in cancer therapy. Nonetheless, it often fails and the reasons for this are not entirely clear. One aspect contributing to therapy failure appears to be competition for scarce nutrients in the tumour microenvironment (TME). This has been shown for some nutrients, including glucose, some amino acid and select vitamins. A systematic study of the vitamin requirements for T cell activation, and potential competition for these vitamins in the TME is, however, missing. In this proposal we will thus: 1. Benchmark the requirements for vitamins in T cell activation, 2. Study potential vitamin competition in the TME, and 3. Assess whether increasing uptake potential for vitamins enhances T cell activity. We will do so by combining in vitro activation assays of primary T cells under varying nutrient conditions, with genetic manipulation of primary T cells. We will perform in depth analysis of both the metabolome as well as the transcriptome to fully understand changes in metabolism and cell function. Additionally, we will develop a murine tumour model of targeted immune attack, wherein we can manipulate nutrient competition for specific vitamins. This will allow us to uncover the effects of competition for B-class vitamins between the tumour and the immune system, as well as finding ways in which the metabolism of immune cell can be changed in a way to better counteract the tumour. To study these effects quantitatively, we will also resort to spatial metabolomics. Using mass spectrometric imaging (MSI) techniques, we will follow the metabolism of tumour and immune cells at a single cell resolution. This will allow us to precisely visualise the effects of our genetic interventions and measure relative competition between the tumour and immune cells at an unprecedented depth. Overall, this proposal will provide mechanistic insights into tumour biology and introduce new potential therapeutic interventions for a sustained anti-tumour immune response.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Achim Tresch