A new study has uncovered a crucial metabolic switch in T cells of the immune system that plays a significant role in creating memory T cells, which provide long-term immunity against previously encountered pathogens, and in a T cell subtype associated with tumors that enhances anti-tumor responses during immunotherapy.
Conducted by researchers Ping-Chih Ho and Alessio Bevilacqua from Ludwig Lausanne, and published in the latest issue of Science Immunology, the study highlights PPARβ/δ, a key regulator of gene expression, as this important molecular switch. The team found that when this switch is not functioning correctly, T cells struggle to retain “memory” of past viral infections and to initiate immune responses against cancer in mice.
“Our results hint that we could pharmacologically target this switch to boost the effectiveness of cancer immunotherapies,” remarked Ho.
When CD8+ T cells, which are responsible for destroying infected and cancerous cells, encounter their target antigens, they activate metabolic pathways that are typically used by healthy cells only in low-oxygen conditions. This form of metabolism, called aerobic glycolysis, is vital for the killer T cells’ ability to grow and eliminate their targets.
Generally, most CD8+ T cells die after they eliminate an infection. However, a select few transition into central memory CD8+ T cells (Tcms) that remain in the body to ensure rapid and effective responses if the same pathogen appears again. To become Tcms, T cells deactivate aerobic glycolysis and adjust their metabolism for long-term persistence in tissues or the bloodstream. The precise mechanisms behind this transformation had previously remained unclear.
Recognizing that PPARβ/δ activates many metabolic processes seen in Tcms, Ho, Bevilacqua, and their team speculated that it plays a vital role in the formation of Tcms. Their investigation into gene expression data from individuals vaccinated against yellow fever revealed that PPARβ/δ was produced in high quantities in their Tcms, as anticipated.
In studies conducted on mice, they discovered that PPARβ/δ becomes active in T cells as the immune response to a viral infection subsides, rather than during the peak of the response. Moreover, CD8+ T cells could not undergo the metabolic conversion necessary to become circulating Tcms without expressing PPARβ/δ. Disruption of PPARβ/δ expression reduced the survival of these Tcms and resident memory T cells in the intestines after infection.
The researchers demonstrated that exposure to interleukin-15—an immune factor crucial for Tcm development—and the expression of a protein named TCF1 engaged the PPARβ/δ pathway. TCF1 is already recognized for its importance in the rapid expansion of Tcms when facing their target pathogen, and this study confirms its role in maintaining Tcms as well.
Interestingly, TCF1 expression is characteristic of a subgroup of CD8+ T cells known as progenitor-exhausted T cells found in tumors. These progenitor-exhausted T cells can take one of two roads: they either become completely inactive, termed “terminally exhausted” T cells, or, with the right stimulus, they proliferate into “effector” CD8+ T cells that attack cancer cells. Immunotherapies, such as anti-PD-1 antibodies, can provide that necessary stimulus.
Evidence that TCF1 modulates the PPARβ/δ pathway in T cells raised the possibility that it might also be crucial for the development and survival of progenitor-exhausted T cells. The researchers confirmed this hypothesis; deleting the PPARβ/δ gene from T cells resulted in the loss of progenitor-exhausted T cells in a melanoma mouse model. They also showed that the PPARβ/δ pathway helps prevent progenitor-exhausted T cells from moving toward terminal exhaustion.
To explore the therapeutic implications of their discoveries, Ho, Bevilacqua, and their colleagues treated T cells with a molecule that stimulates PPARβ/δ activity and tested these treated cells against a melanoma mouse model. The treated T cells were more effective at slowing tumor growth compared to untreated ones and exhibited biochemical characteristics of progenitor-exhausted T cells ready to produce cancer-fighting descendants.
“Given these findings,” Bevilacqua stated, “we propose that targeting PPARβ/δ signaling could be a viable strategy to enhance T cell-mediated anti-tumor immunity.”
Future research will be needed to determine how this strategy could be effectively implemented in humans, a pursuit that the Ho laboratory will continue.
This research was funded by Ludwig Cancer Research, the Swiss National Science Foundation, the European Research Council, the Swiss Cancer Foundation, the Cancer Research Institute, Helmut Horten Stiftung, the Melanoma Research Alliance, the Taiwan Ministry of Science and Technology, the NYU Abu Dhabi Research Institute Award, and Academia Sinica.
Ping-Chih Ho is affiliated with the Lausanne Branch of the Ludwig Institute for Cancer Research and is a full professor at the University of Lausanne.
