A class of drugs targeting a protein found in the endoplasmic reticulum could be effective against B-cell malignancies, according to a study published in Cancer Research.
The protein, STING, plays a critical role in producing type I interferons that help regulate the immune system.
Previous research suggested that STING agonists can improve immune responses when used in cancer immunotherapy or as vaccine adjuvants.
However, the way B cells respond to STING agonists was not well understood.
Chih-Chi Andrew Hu, PhD, of The Wistar Institute in Philadelphia, Pennsylvania, and his colleagues conducted a study to gain some insight.
The researchers found that normal B cells respond to STING agonists by undergoing mitochondria-mediated apoptosis, and STING agonists induce apoptosis in
malignant B cells through binding to STING.
STING agonists proved cytotoxic to B-cell leukemia, lymphoma, and multiple myeloma in vitro. But the drugs did not induce apoptosis in solid tumor malignancies or normal T cells.
The research also revealed that the IRE-1/XBP-1 stress response pathway is required for normal STING function. And B-cell leukemia, lymphoma, and myeloma require the IRE-1/XBP-1 pathway to be activated for survival.
Stimulation by STING agonists suppressed the IRE-1/XBP-1 pathway, which increased the level of apoptosis in malignant B cells.
The researchers confirmed these results in animal models, as treatment with STING agonists led to regression of chronic lymphocytic leukemia and multiple myeloma in mice.
“This specific cytotoxicity toward B cells strongly supports the use of STING agonists in the treatment of B-cell hematologic malignancies,” said Chih-Hang Anthony Tang, MD, PhD, of The Wistar Institute.
“We also believe that cytotoxicity in normal B cells can be managed with the administration of intravenous immunoglobulin that can help maintain normal levels of antibodies while treatment is being administered. This is something we plan on studying further.”
The Wistar Institute’s business development team is looking for a development partner for the advancement of novel STING agonists in treating B-cell hematologic malignancies.
