T cell metabolism and immunotherapy
Introduction
CD8+ T cells are crucial players of immunity due to their paramount role in killing malignant and virally infected cells. Novel immunotherapy treatments use CD8+ T cells to eradicate cancer. In one of these treatments, the T cells are genetically modified to express artificial receptors that target specific proteins on cancer cells. This CAR-T cell therapy uses patients’ T cells to recognise and fight cancer and achieves up to 90% clinical responses against some blood cancers. However, CAR-T cells usually die early after administration, and their persistence depends on tumour type and production method. CAR-T cell therapy also shows very low efficacy against solid tumours due to low CAR-T cell infiltration within the tumour and the inhospitable tumour microenvironment. Long-lasting CAR-T cells are crucial for successful therapy and preventing disease relapse.
We investigate how to produce fitter CAR-T cells that can persist for longer and infiltrate solid tumours better. My lab aims to advance CAR-T cell therapy by focusing in two main research lines: 1) determine the effects of low oxygenation in the response of CAR-T cells within the tumours and 2) improve the production of current and new CAR-T cells by modulating their genetic background or culturing systems.
Research lines
The Foskolou lab is establishing a research line on T cell metabolism and cancer immunotherapy. The lab aims to improve CAR (chimeric antigen receptor) T cell therapy against solid tumours by better understanding the environment CAR-T cells face both in tumours and in lymphoid organs. Our 2 main research lines are:
1) Understanding how T cells respond to low oxygenation (hypoxia)
Oxygen regulates cell metabolism, function, differentiation, and survival of immune cells. Circulating T cells encounter a wide range of oxygen levels during circulation, since most lymphoid tissues are naturally hypoxic (bone marrow 6% O2, spleens 2.9% O2, thymus 0-2% O2). T cells also face oxygen limitation in solid tumours and inflammatory tissues. Hypoxia affects T cell metabolism, function, and differentiation but the effect of hypoxia on T cell responses is rarely investigated. The Foskolou group aims to determine how low oxygenation can be used to achieve beneficial T cell responses, and to find the mechanisms underlying how severe and continuous hypoxia becomes detrimental. We have recently shown that hypoxia and hypoxia-induced metabolites can alter the T cell differentiation status and enhance anti-tumour activity in CAR-T cell therapies. Uncovering the mechanisms by which hypoxia has both beneficial and detrimental effects can help to design better CAR-T cells with higher persistence and to understand how these CAR-T cells can better handle the tumour microenvironment.
2) Finding new CAR-T cell production methods to increase therapy outcome
We recently showed that CAR-T cells that are maintained in a less differentiated phenotype (i.e., multipotent or central memory T cells) during manufacturing display better expansion, anti-tumour activity and persistence. To create multipotent and central memory CAR-T cells we either genetically modify the CAR-T cells using CRISPR/Cas 9 gene editing or we treat the CAR-T cells with specific inhibitors and metabolites. The targets we currently investigate are epigenetic (TET2, KDMs) and epitranscriptomic modifiers (METTL3, FTO, ALKBH5). Optimising the CAR-T cell culturing and manufacturing conditions has strong potential to advance CAR-T cell immunotherapy.
Funding
- Joghem van Loghem (JvL)
- Cancer Research Amsterdam (CCA)
- Horizon Europe Marie Skłodowska-Curie Actions (MSCA)
Key publications
- Barbieri L, Velica P, Gameiro PA, Cunha PP, Foskolou IP, Rullman E, Bargiela D, Johnson RS, Rundqvist H. Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells. Frontiers in Immunology 2023
- Cunha PP, Bargiela D, Minogue E, Krause LCM, Barbieri L, Brombach C, Gojkovic M, Marklund E, Pietsch S, Foskolou IP, Branco CM, Velica P, Johnson RS. Infiltration of tumours I sregulated by T-cell intrinsic nitric oxide synthesis. Cancer Immunol Res 2022
- Bargiela D, Cunha PP, Velica P, Foskolou IP, Barbieri L, Rundqvist H, Johnson RS. Vitamin B6 Metabolism Determines T Cell Anti-Tumor Responses. Front. Immunol 2022
- Matuleviciute R, Cunha PP, Johnson RS*, Foskolou IP*. TET-driven epigenetic alterations in hypoxia and cancer. The FEBS J. 2021
- Veliça P, Cunha PP, Vojnovic N, Foskolou IP, Bargiela D, Gojkovic M, Rundqvist H, Johnson RS. Modified Hypoxia Inducible Factor expression in CD8+ T cells increases anti-tumor efficacy. Cancer Immunol Res 2021
- Foskolou IP, Barbieri L, Vernet A, Bargiela D, Cunha PP, Veliça P, Suh E, Pietsch S, Matuleviciute R, Rundqvist H, McIntyre D, Smith KGC, Johnson RS. The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T outcome. Blood Adv 2020
- Foskolou IP, Jorgensen C, Leszczynska KB, Olcina MM, Tarhonskaya H, Haisma B, D’Angiolella V, Myers WK, Domene C, Flashman E, Hammond EM. Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication. Molecular Cell 2017
- Foskolou IP, Biasoli D, Olcina MM, Hammond EM. Measuring DNA replication in hypoxic conditions. Tumor Microenvironment. 2016
- Leszczynska KB, Foskolou IP, Abraham AG, Anbalagan S, Tellier C, Haider S, Span PN, O'Neill EE, Buffa FM, Hammond EM. Hypoxia induced p53 modulates both apoptosis and radiosensitivity via AKT. J Clin Invest. 2015
- Olcina MM, Foskolou IP, Anbalagan S, Senra JM, Pires IM, Jiang Y, Ryan AJ, Hammond EM. Replication stress and chromatin context link ATM activation to a role in DNA replication. Molecular Cell 2013
- Foskolou IP, Stellas D, Rozani I, Lavigne MD, Politis PK. Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in p27-Kip1 and Cdc25A. Oncogene 2013
