A Yale-led team has identified a promising new combination immunotherapy to enhance the body's ability to fight chronic viral infections and possibly cancer.
Their study was published March 23 in Nature Medicine.
Viruses that cause chronic infection, such as HIV and Hepatitis B and C, are able to persist in the body despite attack from T cells, the body's main line of defense against pathogens. They persist because, over time, our T cells weaken to the point of "T-cell exhaustion." To circumvent this process, the research team—led by Susan Kaech, associate professor of immunobiology at Yale School of Medicine—investigated two pathways that cause T cell suppression.
The first pathway is triggered by prostaglandin E2 (PGE2), a lipid known to suppress the immune system's response to tumors. To explore the relationship between PGE2 and T cells, the research team studied mice with viral infections and observed that PGE2 levels increased, particularly during chronic infection. The enhanced PGE2 reduced both the number of T cells that attack the infected cells and their anti-viral functions.
As Kaech explained, T cells have receptors keeping them in balance by telling them to either stop or go. "What we have discovered is that PGE2 is another type of receptor giving a stop signal," said Kaech, who is also a member of Yale Cancer Center. In fact, when the team studied mice lacking PGE2 receptors, or the ability to synthesize normal amounts of PGE2, T cells thrived.
The researchers next tested the combined effect of systemically reducing PGE2 while simultaneously blocking another pathway known as PD-1. In previous studies, PD-1 had also been shown to inhibit T cells. The researchers treated virus-infected mice lacking normal PGE2 production with anti-PD-1 antibodies, and observed that the combined blockade of PGE2 and PD-1 resulted in even greater increased T-cell function and enhanced viral control.
"Blocking both pathways leads to an augmentation of the antiviral response that is bigger than either treatment alone," Kaech explained.
In a final step, the researchers found they could achieve the same boost to T cells by administering celecoxib (Celebrex), a non-steroidal anti-inflammatory drug (NSAID) commonly used to manage pain. "Since these inhibitors are already in common use, we wondered if using them to decrease PGE2 signaling would also improve T-cell responses," said Jonathan Chen, first author on the study and a resident in pathology at Massachusetts General Hospital.
One important implication of the study is the potential use of NSAIDs as adjunct therapy to treat patients with chronic infections and cancer. "By administering a medicine many of us take routinely, we could potentially augment the effects of PD-1 blockade, which is showing remarkable outcomes in cancer trials," said Kaech.
Explore further: By taking a rest, exhausted T cells live to fight another day
More information: Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection, Nature Medicine, http://ift.tt/1GLy5HV
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A Yale-led team has identified a promising new combination immunotherapy to enhance the body's ability to fight chronic viral infections and possibly cancer.
Their study was published March 23 in Nature Medicine.
Viruses that cause chronic infection, such as HIV and Hepatitis B and C, are able to persist in the body despite attack from T cells, the body's main line of defense against pathogens. They persist because, over time, our T cells weaken to the point of "T-cell exhaustion." To circumvent this process, the research team—led by Susan Kaech, associate professor of immunobiology at Yale School of Medicine—investigated two pathways that cause T cell suppression.
The first pathway is triggered by prostaglandin E2 (PGE2), a lipid known to suppress the immune system's response to tumors. To explore the relationship between PGE2 and T cells, the research team studied mice with viral infections and observed that PGE2 levels increased, particularly during chronic infection. The enhanced PGE2 reduced both the number of T cells that attack the infected cells and their anti-viral functions.
As Kaech explained, T cells have receptors keeping them in balance by telling them to either stop or go. "What we have discovered is that PGE2 is another type of receptor giving a stop signal," said Kaech, who is also a member of Yale Cancer Center. In fact, when the team studied mice lacking PGE2 receptors, or the ability to synthesize normal amounts of PGE2, T cells thrived.
The researchers next tested the combined effect of systemically reducing PGE2 while simultaneously blocking another pathway known as PD-1. In previous studies, PD-1 had also been shown to inhibit T cells. The researchers treated virus-infected mice lacking normal PGE2 production with anti-PD-1 antibodies, and observed that the combined blockade of PGE2 and PD-1 resulted in even greater increased T-cell function and enhanced viral control.
"Blocking both pathways leads to an augmentation of the antiviral response that is bigger than either treatment alone," Kaech explained.
In a final step, the researchers found they could achieve the same boost to T cells by administering celecoxib (Celebrex), a non-steroidal anti-inflammatory drug (NSAID) commonly used to manage pain. "Since these inhibitors are already in common use, we wondered if using them to decrease PGE2 signaling would also improve T-cell responses," said Jonathan Chen, first author on the study and a resident in pathology at Massachusetts General Hospital.
One important implication of the study is the potential use of NSAIDs as adjunct therapy to treat patients with chronic infections and cancer. "By administering a medicine many of us take routinely, we could potentially augment the effects of PD-1 blockade, which is showing remarkable outcomes in cancer trials," said Kaech.
Explore further: By taking a rest, exhausted T cells live to fight another day
More information: Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection, Nature Medicine, http://ift.tt/1GLy5HV
Medical Xpress on facebook
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By taking a rest, exhausted T cells live to fight another day
Killer T cells are one of the body's main lines of defense against pathogens. Their job is to kill infected cells so that the viruses inside cannot replicate and spread. But often the force of their attack ...
Researchers find that influenza has an Achilles' heel
Flu epidemics cause up to half a million deaths worldwide each year, and emerging strains continually threaten to spread to humans and cause even deadlier pandemics. A study published by Cell Press on April 10 in the journal ...
Stem cells derived from amniotic tissues have immunosuppressive properties
Stem cells derived from human amnion have for some time been considered promising for cell therapies because of their ease of access, ability to differentiate, and absence of ethical issues. Now, a Japanese research team ...
'Wound response' of cancer stem cells may explain chemo-resistance in bladder cancer
A novel mechanism - similar to how normal tissue stem cells respond to wounding - might explain why bladder cancer stem cells actively contribute to chemo-resistance after multiple cycles of chemotherapy ...
Study identifies low-dose aspirin's mechanisms of action in reducing cancer mortality
Low-dose aspirin may lower the risk for cancer metastasis and mortality by inhibiting both COX-1 and COX-2 pathways, according to data presented at the 13th Annual AACR International Conference on Frontiers in Cancer Prevention ...
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