A recent study conducted by Ludwig Cancer Research has identified a crucial metabolic switch in the immune system’s T cells that is essential for the generation of memory T cells, which provide lasting immunity to previously encountered pathogens. The study, led by Ludwig Lausanne researchers Ping-Chih Ho and Alessio Bevilacqua and published in Science Immunology, has identified PPARβ/δ as the master regulator of gene expression responsible for this molecular switch. Dysfunctional PPARβ/δ has been shown to compromise T cell memory and the induction of anticancer immune responses in mice, leading researchers to suggest that pharmacological targeting of this switch could improve the efficacy of cancer immunotherapies.
When killer T cells are activated by their target antigens, they switch on metabolic pathways involving aerobic glycolysis to support their ability to proliferate and destroy target cells. After clearing an infection, some killer T cells transform into central memory T cells (Tcms) that confer immunity by establishing a swift and lethal response upon re-encounter with the same pathogen. The process of Tcm formation involves the activation of PPARβ/δ in T cells during the waning phase of the immune response to viral infection. T cells that fail to express PPARβ/δ are unable to make the metabolic switch required to become circulating Tcms, disrupting their survival and the persistence of memory T cells in tissues.
Researchers discovered that T cell exposure to interleukin-15, an immune factor crucial for Tcm formation, and the expression of TCF1 protein engage the PPARβ/δ pathway. TCF1, known for its role in the expansion of Tcms, is also important for the maintenance of Tcms. Furthermore, TCF1 expression is associated with a subset of CD8+ T cells known as progenitor-exhausted T cells found in tumors. These T cells can either become terminally exhausted or differentiate into effector CD8+ T cells that kill cancer cells upon receiving the appropriate stimulus, such as checkpoint blockade immunotherapies like anti-PD-1 antibodies.
The study demonstrates that TCF1 modulates the PPARβ/δ pathway in T cells, suggesting its critical role in the formation and maintenance of progenitor-exhausted T cells found in tumors. Deleting the PPARβ/δ gene in T cells resulted in the loss of progenitor-exhausted T cells in a mouse melanoma model. Additionally, experiments involving exposure of T cells to a molecule stimulating PPARβ/δ activity showed increased efficiency in delaying melanoma tumor growth in mice, indicating the potential for enhancing T cell-mediated anti-tumor immunity by targeting PPARβ/δ signaling.
The researchers propose that targeting PPARβ/δ signaling could be a promising strategy to improve T cell-mediated anti-tumor immunity. However, further studies are needed to explore the therapeutic potential of this approach in humans. The study, supported by various funding sources including Ludwig Cancer Research, the Swiss National Science Foundation, the European Research Council, and others, sheds light on the molecular mechanisms underpinning memory T cell formation and anti-tumor responses, offering new insights into potential targets for cancer immunotherapies. Ping-Chih Ho, a member of the Lausanne Branch of Ludwig Institute for Cancer Research, and his team plan to further investigate the implications of their findings for developing novel therapeutic approaches.