Northwestern Medicine investigators have discovered new intracellular mechanisms that help specialized immune cells adapt and respond to disease and acute inflammation, findings that may inform the development of targeted therapies for cancer and tissue injury, according to a recent study published in the Journal of Clinical Investigation.
Benjamin Singer, ’07 MD, ’10 GME, the Lawrence Hicks Professor of Pulmonary Medicine, and Samuel Weinberg, ‘19 MD, ‘19 PhD, assistant professor of Pathology in the Division of Experimental Pathology, were co-senior authors of the study.
Regulatory T-cells, or Treg cells, regulate the body’s immune response to cancer and acute inflammation from infection or tissue injury. In cancer, Tregs suppress anti-tumor immune responses and are therefore a common immunotherapy target.
To function properly, Treg cells require mitochondrial metabolism, the process by which mitochondria generate energy in the form of ATP and signals that regulate cell function. The mechanisms by which Treg cells regulate their acute immune responses in metabolically stressed microenvironments, such as those caused by cancer or infection, however, has remained unclear.
In the current study, the investigators sought to determine whether Treg cells require the enzyme AMPK, a key regulator of cellular metabolism, to properly function in metabolically stressed microenvironments by studying mouse models of melanoma and viral pneumonia.
“AMPK is like the fuel gauge for the cell,” said Singer, who is also an associate professor of Biochemistry and Molecular Genetics. “It senses when the cell is running low on energy and then it does a number of things to promote energy-replenishing processes so that the cell can function.”
Using a combination of -omics techniques, the scientists discovered that in harsh metabolic environments, AMPK essentially rewires Treg cell metabolism to support proper Treg cell function.
In the mouse models of melanoma, the scientists found that AMPK regulates DNA methyltransferase 1, an enzyme that maintains DNA methylation, to promote transcriptional programs associated with mitochondrial function in the tumor microenvironment. In mice with viral pneumonia, they found that AMPK sustains metabolic function and mitochondrial activity.
The findings demonstrate how AMPK allows Treg cells to adapt to microenvironmental stress through mitochondrial metabolism, findings that may help identify future potential drugs targets that modulate Treg cell function in cancer and tissue injury according to Singer.
“We identified that AMPK regulates mitochondrial function through epigenetic mechanisms in Treg cells, but we have a lot of gaps to fill in terms of what the specific up- and downstream pathways are and whether they themselves could also be drug targets,” Singer said.
Manuel Torres Acosta, an MD/PhD student in the Medical Scientist Training Program (MSTP), was lead author of the study.
This work was supported by National Institutes of Health (NIH) awards T32GM144295, T32HL076139, F31HL162490, T32GM144295 and T32HL076139; the David W. Cugell Fellowship and The Genomics Network (GeNe) Pilot Project Funding; NIH awards T32AI083216, T32HL076139, F32HL162418, K08HL159356, U19AI135964; the Parker B. Francis Opportunity Award; NIH award T32GM144295; the Burroughs Wellcome Fund Career Awards for Medical Scientists; and NIH awards R01HL149883, R01HL153122, P01HL154998, P01AG049665, U19AI135964, and U19AI181102.
