Inhibition of the STING Protein Pathway Can Prevent Patients from Developing Graft-versus-host Disease

In a new study, researchers found that inhibiting the STING protein pathway can protect some patients from graft versus host disease (GVHD), among which, GVHD is the most serious complication of bone marrow (stem cell) transplantation. The relevant research results were published in the journal Science Translational Medicine. The title of the paper is “STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets”.

 

Dr. Levy said, “This pathway plays a very important role in allogeneic (donor) stem cell transplantation. In a preclinical model that simulates transplantation between HLA (human leukocyte antigen) matched patients, we want to interfere with the STING pathway to minimize GVHD and the complications associated with this disease.”

 

Given that aggressive chemotherapy is used to destroy the patient’s own bone marrow cells, allogeneic bone marrow transplantation, where the patient obtains new hematopoietic cells from a donor, is usually a major part of the treatment of leukemia and lymphoma. However, the donor’s cells can also produce their own immune response, allowing these transplanted cells to fight against their new host. GVHD can cause skin rash, nausea, diarrhea, and liver damage, and is the main non-recurrent cause of death in these patients.

 

 

In this paper, Dr. Levy and his research team tested whether STING can be adjusted to control GVHD. In one example, they constructed an animal model of allotransplantation that mimics sibling match and found that when STING is missing, the symptoms of GVHD are reduced. However, when STING is studied in a transplantation model that does not match the donor and recipient because the donor and recipient are not closely related, the absence of the STING pathway can worsen GVHD.

 

Further studies have shown that this surprising difference is caused by different immune system T cells. When only CD8 T cells were transplanted but not CD4 T cells, Levy’s laboratory replicated the positive results in the unmatched transplant model, reducing the symptoms of GVHD.

 

Dr. Levy said, “This tells us that the cell population that mediates GVHD does affect the role of STING in these grafts. STING can worsen GVHD, or it can also provide protection. We found that when CD8 T cells are present in the transplant, they will remove the antigen-presenting cells that activate CD4 T cells when they are in the medium. Therefore, if you remove these antigen-presenting cells, CD4 T cells will not be activated, and you can reduce GVHD.”

 

Dr. Levy believes that suppressing STING in matched patients may reduce their risk of GVHD. However, there may be an additional benefit: STING can also be enhanced to activate T cells and promote a stronger immune response to cancer cells. In this case, clinicians may want to selectively inhibit and enhance STING at different times when treating cancer patients.

 

Dr. Levy said, “For matched compatriots, just like our preclinical model, we want to block STING early in the transplant to prevent severe GVHD from appearing. Later, we may want to deactivate STING to helps generate an anti-tumor immune response against residual leukemia or lymphoma cells.”

 

 

Reference

1. Cameron S. Bader et al. STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets. Science Translational Medicine, 2020, doi:10.1126/scitranslmed.aay5006.

2. Sylvester researchers identify protein target that might ease graft versus host disease. https://medicalxpress.com/news/2020-07-sylvester-protein-ease-graft-host.html