A Ludwig Cancer Research study has identified a metabolic switch in immune system T cells that is essential for the generation of memory T cells (which confer long-lasting immunity to previously encountered pathogens) and a T cell subtype found in tumors that drives anti-tumor responses during immunotherapy.
Directed by Ping-Chih Ho and Alessio Bevilacqua of Ludwig Lausanne and published in the current issue of Science ImmunologyThe study identifies PPARβ/δ, a master regulator of gene expression, as that essential molecular switch. Ho, Bevilacqua and their colleagues also demonstrate that dysfunction of the switch compromises T cell “memory” of previously encountered viruses, as well as the induction of anti-cancer immune responses in mice.
“Our findings suggest that we could pharmacologically activate this switch to improve the efficacy of cancer immunotherapies,” Ho said.
When killer T cells (or CD8+ cells), which kill diseased and cancerous cells, are activated by their target antigen, they activate metabolic pathways that most other healthy cells only use when they lack oxygen. This type of metabolism (which involves a metabolic process known as aerobic glycolysis) supports multiple processes essential to the ability of killer T cells to proliferate and destroy their target cells.
Most killer T cells die after they have cleared an infection. However, a few transform into central memory CD8+ T cells (CMCs) that remain in the circulation to establish what we call immunity: the ability to mount a rapid, lethal response to the same pathogen if it is ever encountered again. To achieve this transformation, T cells turn off aerobic glycolysis and adapt their metabolism to persist long-term in tissues or circulation. Until now, exactly how they do this has been unknown.
Aware that PPARβ/δ activates many of the metabolic processes characteristic of Tcms, Ho, Bevilacqua, and colleagues hypothesized that it might play a key role in Tcm formation. They examined immunological gene expression data collected from yellow fever vaccine recipients long after vaccination and, as expected, found that PPARβ/δ was abundantly produced in their Tcms.
Their studies in mice revealed that PPARβ/δ is activated in T cells not at the peak phase of the immune response to viral infection, but rather when the response is waning. Furthermore, CD8+ T cells could not undergo the metabolic switch required to become circulating T cells if they did not express PPARβ/δ. Disruption of its expression impaired the survival of these T cells and of gut-resident memory T cells after infection.
Researchers show that exposure of T cells to interleukin-15 (an important immune factor for T cell formation) and their expression of a protein called TCF1 activates the PPARβ/δ pathway. TCF1 is already known to be critical for the rapid expansion of T cells when they encounter the target pathogen. In this study, the researchers show that it is also important for T cell maintenance.
In fact, TCF1 expression is a hallmark of a subset of CD8+ T cells (exhausted progenitor cell T cells) found in tumors. These exhausted progenitor cell T cells follow one of two paths: either they become completely lethargic, “terminally exhausted” T cells; or, if given the right stimulus, they proliferate to produce “effector” CD8+ T cells that kill cancer cells. Checkpoint blockade immunotherapies, such as anti-PD-1 antibodies, can provide such a stimulus.
The observation that TCF1 modulates the PPARβ/δ pathway in T cells raised the possibility that it might also be essential for the formation and maintenance of progenitor-exhausted T cells. The researchers showed that this is indeed the case. Deleting the PPARβ/δ gene from T cells led to the loss of progenitor-exhausted T cells in a mouse model of melanoma. They also showed that the PPARβ/δ pathway reduces the tendency of progenitor-exhausted T cells to stagger toward 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 slowed melanoma tumor growth in mice more efficiently than their untreated counterparts and had biochemical characteristics of exhausted progenitor T cells primed to generate cancer-killing offspring.
“Based on these findings,” Bevilacqua said, “we suggest that targeting PPARβ/δ signaling may be a promising approach to enhance T cell-mediated antitumor immunity.
How exactly this might be achieved in people is a topic of further study that will no doubt be continued by Ho’s lab.
This study was supported by Ludwig Cancer Research, the Swiss National Science Foundation, European Research Council, Swiss Cancer Foundation, Cancer Research Institute, Helmut Horten Foundation, Melanoma Research Alliance, Ministry of Science and Technology of Taiwan, New York University 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 senior lecturer at the University of Lausanne.