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Oct 27, 2016
 |  BC Innovations  |  Targets & Mechanisms

T cell gas, tumor brake

Three studies pump the therapeutic potential of PGC-1α

A trio of studies has converged on a common pathway, headed by the PPAR co-activator PGC-1α, to fight cancer and chronic infections by manipulating either T cell immunotherapies or the tumors themselves. While the findings reveal new biology underlying T cell exhaustion, they could also open the door to therapeutics against a hitherto under-exploited target.

PGC-1α is a transcriptional co-activator commonly referred to as the “master regulator of mitochondrial biogenesis.” Its overexpression has been shown to improve outcomes in preclinical models of a wide range of diseases, including atherosclerosis, acute kidney injury (AKI) and cancer, although some studies have shown the opposite - by demonstrating high PGC-1α activity helps tumor cells thrive.

The regulator lies downstream of a wide range of signaling pathways, including SIRT1, AMPK and nitric oxide (NO) synthases. As a co-activator, it helps transcription factors such as PPARγ, PPARα and NRF2 induce expression of genes that promote mitochondrial biogenesis, fatty acid oxidation, and protection from reactive oxygen species.

While several PGC-1α activators and co-regulators have been targeted commercially for treatment of metabolic, cardiovascular and other diseases, no companies have disclosed clinical programs directly targeting PGC-1α.

Now, three papers from groups at the University of Pennsylvania, University of Pittsburgh and Dana-Farber Cancer Institute have found new opportunities in the PGC-1α axis for treating viral infections or cancer.

In two of the studies, published in Immunity, cranking up PGC-1α expression helped T cells avoid exhaustion in cancer or chronic infection, while in the third, published in Nature, up-regulating its non-metabolic functions in tumor cells stemmed the formation of cancer metastases (see “Both Sides Now,” page 8).

Fuel for the long haul

In the Immunity papers, collaborating teams led by UPenn’s John Wherry and Pittsburgh’s Greg Delgoffe showed T cells battling chronic infections and cancer shared a metabolic pathology that was alleviated by PGC-1α up-regulation, which helped T cells dodge exhaustion in both settings.

Wherry is director of UPenn’s Institute for Immunology and Delgoffe is a professor of immunology.

The duo found the commonality when they observed that T cells in the two diseases exhibited similar phenotypes of mitochondrial dysfunction, shedding new light on a long-standing phenomenon in the field.

“What was thought for many years is...

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