The word sting is usually associated with a quick sharp pain or hurt, but sting may now be associated with protection. Researchers from the Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine have discovered that the STING protein pathway can protect certain patients from graft versus host disease (GvHD).

Their study, “STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets,” is published in Science Translational Medicine and led by Robert Levy, PhD, professor of microbiology and immunology at the University of Miami Miller School of Medicine.

Stimulator of interferon genes (STING) is a signaling molecule associated with the endoplasmic reticulum (ER) and is essential for controlling the transcription of numerous host defense genes, including type I interferons (IFNs) and pro-inflammatory cytokines. STING signaling has been previously reported to be essential for protecting the cell against a variety of pathogens and even against the development of cancer by promoting antitumor immune responses.

Researchers at the University of Miami Miller School of Medicine tested whether STING could be regulated to control GvHD, a serious complication in bone marrow stem cell transplants. GvHD is a potentially life-threatening medical condition that is common after allogeneic hematopoietic stem cell transplantation (HSCT), the only curative treatment for various types of leukemias. The donated bone marrow or stem cells view the recipient’s body as foreign, and the donated cells/bone marrow attack the body. The two types of GvHD are acute and chronic.

“The STING pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and GvHD after major histocompatibility complex (MHC)–mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect is clinically relevant MHC-matched aHSCT is unknown,” wrote the researchers.

“This pathway is very important in allogeneic (donor) stem cell transplants,” explained Levy.

The researchers created an animal model that replicates an allogeneic transplant from a sibling match and found that when STING was absent, the symptoms of GvHD were reduced. But when investigating STING in an unmatched transplant model, the absence of the pathway made GvHD worse.

“Further examination revealed that STING deficiency reduced the activation of donor CD8+ T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4+T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity,” wrote the researchers.

The team of researchers learned that populations that mediate GVHD affect the role STING plays in the transplants. “STING can worsen GVHD or it can provide a protective effect. We figured out that, when the CD8+T cells are present in the transplant, they get rid of the antigen-presenting cells that drive CD4+T cells. So, if you get rid of those antigen-presenting cells, and you don’t drive CD4+T cells, you can also mitigate GVHD,” noted Levy.

“With matched siblings, like our preclinical model, we would want to block STING during the early part of the transplant to prevent serious graft versus host disease,” stated Levy. “Then later, we might want to go in and activate STING to help generate tumor immunity against the remaining leukemia or lymphoma cells.”

Their results showed that inhibiting STING in matched patients have the potential to reduce the risks of developing GvHD. Another added benefit may be that STING may be regulated to activate T cells and promote a strong immune response against cancer.

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