Cancer immunotherapies employ functional T cell responses to be effective. T-cell therapy is a form of immunotherapy that uses specially altered T cells to fight cancer.
However, tumor cells and immune cells within the tumor microenvironment can disrupt T cell functionality using several strategies. For instance, tumor cells and regulatory T cells cause senescence of functional T cells, limiting their ability to kill tumor cells.
Regulatory T (TReg) cells are essential for maintaining peripheral tolerance, preventing autoimmunity, and limiting chronic inflammatory diseases. However, they also limit beneficial responses by suppressing sterilizing immunity and limiting anti-tumor immunity.
The presence of Treg cells has been shown to correlate with a poor prognosis in several tumor types in large population-based studies. This is supported by a study on breast cancer patients wherein individuals with high numbers of Treg cells in their tumors had a shorter relapse-free and overall survival than those with low Treg-cell infiltrate.
The control of lipid metabolism is central to T lymphocytes’ appropriate differentiation and functions and ultimately to the maintenance of immune tolerance.
Lipid metabolism is the synthesis and degradation of lipids in cells, involving the breakdown or storage of fats for energy and the synthesis of structural and functional lipids. These fats are obtained from food or are synthesized by the liver.
In this research, the authors looked into the development of T cell senescence driven by both malignant tumor cells and regulatory T cells mediated by dysregulation of lipid metabolism by conventional T cells.
Read the original publication of this study here: [ Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy ]
Learn about the significant link between balancing lipid metabolism and t cell senescence in cancer immunotherapy and maintenance of immune tolerance.
Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy
Cellular metabolism, encompassing lipid metabolism, controls T cell survival, differentiation, and effector functions. T cells in their functional state are the key determinant for effective anti-tumor immunity and immunotherapy.
Researchers assessed that cancers, in general, feature the development of T cell senescence driven by both malignant tumor cells and regulatory T cells. These senescent T cells have active glucose metabolism but exhibit unbalanced lipid metabolism.
The imbalance in lipid metabolism induces lipid metabolic enzyme expressions, which cause alterations in lipid species and accumulation of lipid droplets in T cells.
Tumor cells and Treg cells drive elevated group IVA phospholipase A2 expression, an enzyme that initiates the arachidonic acid pathway and plays a vital role in inflammation. In the context of this study, Group IVA phospholipase A2 was responsible for the changed lipid metabolism and senescence induction in T cells.
In mouse models of melanoma and breast cancer, the inhibition of group IVA phospholipase A2 reprogrammed effector T cell lipid metabolism prevented T cell senescence in vitro. More importantly, this resulted in enhanced anti-tumor immunity and immunotherapy efficacy.
The authors showed that normalizing lipid metabolism and reversing senescence resulted in better control of tumor burden and extended survival of melanoma and breast cancer. Together, these findings identify mechanistic links between T cell senescence and regulation of lipid metabolism in the tumor microenvironment and may further improve cancer immunotherapies.
Takeaways:
- Tumor cells and regulatory T cells induce senescence of conventional T cells, limiting their ability to kill tumor cells
- Normalizing lipid metabolism and reversing senescence resulted in better control of tumor burden and extended survival in mouse models of melanoma and breast cancer.
- Targeting lipid metabolism may further improve cancer immunotherapies.
- [ Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy ]
- [ Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse ]
- [ The Role of Lipid Metabolism in T Lymphocyte Differentiation and Survival ]