A Ludwig Cancer Research study has identified a metabolic switch in the immune system’s T cells that is essential for the generation of memory T cells—which confer lasting immunity to previously encountered pathogens—and a subtype of T cells found in tumors that leads to anti-tumor responses during immunotherapy.
Led by Ping-Chih Ho and Alessio Bevilacqua of Ludwig Lausanne and published in its current issue Science Immunologythe study identifies PPARβ/δ, a master regulator of gene expression, as this key molecular switch. Ho, Bevilacqua and colleagues also show that dysfunction of the switch compromises T cell “memory” of previously encountered viruses as well as the induction of antitumor immune responses in mice.
Our findings suggest that we may be able to use this switch pharmacologically to improve the effectiveness of cancer immunotherapies.”
Ping-Chih Ho, Ludwig Lausanne
When killer (or CD8+) T cells, which kill diseased and cancer cells, are activated by their target antigen, they activate metabolic pathways that most other healthy cells use only when starved for oxygen. This type of metabolism—which includes a metabolic process known as aerobic glycolysis—supports multiple processes necessary for the killer T cell’s ability to proliferate and destroy its target cells.
Most killer T cells die after clearing an infection. Some, however, transform into central memory CD8+ T cells (Tcms) that remain in the circulation to generate what we call immunity: the ability to mount a rapid and lethal response to the same pathogen if re-encountered. To achieve this transformation, T cells shut down aerobic glycolysis and otherwise adapt their metabolism to remain long-term in tissues or circulation. Exactly how much they do this has so far been unknown.
Knowing that PPARβ/δ activates many of the metabolic processes characteristic of Tcms, Ho, Bevilacqua and colleagues hypothesized that it may play a key role in Tcm formation. They looked at immune gene expression data collected from yellow fever vaccine recipients long after vaccination and, as expected, saw that PPARβ/δ was abundantly produced in their Tcms.
Their studies in mice revealed that PPARβ/δ is activated in T cells not during the peak phase of the immune response to viral infection, but as that response wanes. Furthermore, CD8+ T cells were unable to make the metabolic switch required to become circulating Tcms if they failed to express PPARβ/δ. Disruption of its expression reduced the survival of such Tcms and resident memory T cells in the gut after infection.
The researchers show that exposure of T cells to interleukin-15-, an immune factor important for Tcm- formation, and their expression of a protein called TCF1 engages the PPARβ/δ pathway. TCF1 is already known to be critical for the rapid expansion of Tcms when they encounter their pathogenic target. The researchers show in this study that it is also important for the maintenance of TCMs.
As it happens, TCF1 expression is a hallmark of a subset of CD8+ T cells—progenitor-depleted T cells—found in tumors. These progenitor-exhausted T cells follow one of two pathways: they either become completely dormant, “finally exhausted” T cells. or, given the right stimulus, proliferate to produce “active” CD8+ T cells that kill cancer cells. Checkpoint-blocking immunotherapies, such as anti-PD-1 antibodies, can provide such a stimulus.
The observation that TCF1 regulates the PPARβ/δ pathway in T cells raised the possibility that it may also be necessary for the formation and maintenance of progenitor-depleted T cells. Researchers have shown that this is indeed the case. Deletion of the PPARβ/δ gene from T cells resulted in the loss of progenitor-depleted T cells in a murine model of melanoma. They also demonstrate that the PPARβ/δ pathway limits the propensity of progenitor-depleted T cells to escalate to terminal exhaustion.
To assess the therapeutic potential of their findings, Ho, Bevilacqua and colleagues exposed T cells to a molecule that stimulates PPARβ/δ activity and used the treated cells against a mouse model of melanoma. These cells delayed the growth of melanoma tumors in mice more effectively than their untreated counterparts and bore biochemical characteristics of ancestral exhausted T cells primed to give rise to cancer-killing progeny.
“Based on these findings,” Bevilacqua said, “we suggest that targeting PPARβ/δ signaling may be a promising approach to improve T cell-mediated antitumor immunity.
Exactly how this can be achieved in humans is a topic for further study that will no doubt be pursued by the Ho lab.
This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, the European Research Council, the Swiss Cancer Foundation, the Institute for Cancer Research, the Helmut Horten Foundation, the Melanoma Research Alliance, the Ministry of Science and Technology of Taiwan, NYU Abu Dhabi Research Institute Award and Academia Sinica.
Ping-Chih Ho is a member of the Lausanne Branch of the Ludwig Institute for Cancer Research and a full professor at the University of Lausanne.
Source:
Journal Reference:
Bevilacqua, A., et al. (2024) Orchestrated PPARβ/δ metabolic reprogramming supports the formation and maintenance of memory CD8+ T cells. Science Immunology. doi.org/10.1126/sciimmunol.adn2717.
