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Scientists Discover Surprising Immune Cell Activity That May Limit Immunotherapy

posted Nov 2, 2017, 9:27 AM by Lyssiotis Lab   [ updated Nov 2, 2017, 9:30 AM ]

Suppressive Treg cells become even more suppressive when they die, a new study finds.
Researchers have uncovered a surprising process within a key immune cell that may help explain the limitations of immunotherapy as a cancer treatment.

Regulatory T cells, or Treg cells, work within the immune system to suppress immune function. It’s a normal process: T cells fight an infection, and when the threat is over, Treg cells send the signal to stand down.

Cancer immunotherapy treatments work by supercharging the immune system to fight cancer. So when Tregs come in and suppress the immune response, it shuts down the cancer-fighting effect.

But eliminating the Tregs doesn’t help. Researchers have tried, but a clinical trial testing that idea showed no benefit to patients.

Now, more than a decade after discovering the immunosuppressive role of Tregs in human cancer, a new study in Nature Immunology finds that eliminating the Treg cells doesn’t eliminate their suppressive qualities.

When the Tregs die, instead of being negated, they become even more suppressive. All the cells are dead, but the machine is still running.

“It’s a double-edged sword: If they do not die, they are suppressive. But if they die, they are even more suppressive,” says senior study author Weiping Zou, M.D., Ph.D., the Charles B. de Nancrede Professor of Surgery, Immunology and Biology at the University of Michigan.

“Nobody expected this — it was a total surprise. But it likely explains why you don’t see benefit when you induce Treg apoptosis,” he says.

"It’s a double-edged sword: If they do not die, they are suppressive. But if they die, they are even more suppressive."
Weiping Zou, M.D., Ph.D.


Next steps for the work

Immunotherapy has revolutionized cancer treatment, but limitations and questions remain. One of the biggest questions is why such a small number of patients are responsive.

SEE ALSO: Gaming Cells to Turn Off the Metastases Switch in Breast Cancer

In 2004, Zou’s lab discovered that Treg cells were acting against cancer immunity. The researchers linked higher numbers of these cells to shorter survival in patients. That work led to the failed clinical trial designed to eliminate the Treg cells.

It turns out, this new study finds, that when Treg cells die, they release a lot of small metabolites called ATP. Usually ATP helps supply the body with energy. But dying Tregs quickly convert ATP to adenosine. The adenosine then targets T cells, binding to a receptor on the T cell surface. This affects the function of the T cells, making them unhealthy.

Tregs travel to the tumor from throughout the body, which explains Zou’s earlier finding that there are many Tregs in a tumor. But while the Tregs proliferate, they are dying fast at the same time. So there are many Tregs but also many dying Tregs.

Researchers will next look for ways to limit this function by creating a roadblock to prevent the cells from migrating to the tumor microenvironment. They will also investigate options to block or control the suppressive activity.

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New paper published in PNAS

posted Nov 1, 2017, 10:55 AM by Lyssiotis Lab   [ updated Nov 1, 2017, 10:55 AM ]

A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers
, by Bollong MJ et al. published in Proc Natl Acad Sci U S A on Oct 30, 2017.
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New paper published in Nature Immunology

posted Oct 31, 2017, 12:59 PM by Lyssiotis Lab   [ updated Oct 31, 2017, 12:59 PM ]

Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor, by Tomasz Maj et al. published in Nature Immunology on Oct 30, 2017.












New book chapter published in Imaging and Metabolism

posted Oct 6, 2017, 6:36 AM by Lyssiotis Lab   [ updated Oct 6, 2017, 6:37 AM ]

A Topical Report on the Design Principles of Metabolism, by Costas Lyssiotis et al. published in Imaging and Metabolism.
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New review published in Trends in Cell Biology

posted Jul 25, 2017, 7:19 PM by Lyssiotis Lab   [ updated Oct 6, 2017, 6:36 AM ]

Metabolic Interactions in the Tumor Microenvironment, by Costas Lyssiotis and Alec Kimmelman published in Trends in Cell Biology.
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New paper published in Cell Reports

posted Jul 20, 2017, 5:46 PM by Lyssiotis Lab   [ updated Jul 20, 2017, 5:46 PM ]

Proteomic and Metabolomic Characterization of a Mammalian Cellular Transition from Quiescence to Proliferation
, by Kirschner et al. published in Cell Reports on July 18, 2017.
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New review published in Antioxidants & Redox Signaling

posted Jul 17, 2017, 5:00 AM by Lyssiotis Lab   [ updated Oct 6, 2017, 6:36 AM ]

Emerging roles for SIRT5 in metabolism and cancer
, by Costas Lyssiotis et al. published in Antioxidants & Redox Signaling.
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New paper published in Cancer Cell

posted Jul 12, 2017, 4:28 AM by Lyssiotis Lab   [ updated Jul 12, 2017, 4:28 AM ]

MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer
, by Shukla et al. published in Cancer Cell on July 10, 2017.
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New review published in Journal of Immunology

posted Apr 25, 2017, 5:42 PM by Lyssiotis Lab   [ updated Apr 26, 2017, 6:29 AM ]

Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis
, by Costas Lyssiotis published in Journal of Immunology.
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New review published in Cancer Cell

posted Jan 12, 2017, 8:24 AM by Lyssiotis Lab   [ updated Jan 12, 2017, 8:37 AM by Costas Lyssiotis ]

Employing Metabolism to Improve the Diagnosis and Treatment of Pancreatic Cancer, by Halbrook and Lyssiotis published in Cancer Cell January 9, 2017.

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