Philadelphia, PA (Press Release) – In almost every mammalian cell, you will find the endo­plasmic reticulum, a network of continuous membranes responsible for controlling metabolism as well as the folding, assembly and secretion of proteins. Since the endo­plasmic reticulum is critical in manu­fac­tur­ing important proteins that facilitate communication between cells, researchers are exploring new ways to find important targets within these membranes that could help stimulate immune responses against cancer cells.

Now, new research from The Wistar Institute shows how one protein found on the endo­plasmic reticulum can serve as a target for stimulating the immune system and a more direct target for cellular death in B cell malig­nancies. The findings of the study were published in the journal Cancer Research.

A protein called Stimulator of interferon genes (STING) is found on the endoplasmic reticulum and plays a critical role in producing type I inter­ferons that help regulate the immune system. A new class of drugs called STING agonists were developed to induce powerful immune responses by boosting the pro­duc­tion of interferons as an adjuvant ther­apy, meaning they were applied to en­hance response to ther­apy. Improved immune responses were observed when STING agonists were used in cancer immuno­therapy or as vaccine adjuvants.

As an adjuvant ther­apy, STING agonists play an accessory role in eliciting a response. However, addi­tional studies con­firmed that these drugs also induce apop­tosis in normal and malig­nant B cells, suggesting that they could be used as a pri­mary ther­apy in certain types of leukemia, lym­phoma and multiple myeloma. The responses that have been observed thus far are transient, meaning that longer responses could lead to better direct treat­ment in B cell malig­nancies like chronic lym­pho­cytic leukemia and multiple myeloma.

“In non-B cells, STING agonists stimulate the pro­duc­tion of interferons, but since they induce apop­tosis in B cells, these B cells do not live long enough to help boost the immune response,” said Chih-Chi Andrew Hu, Ph.D., asso­ci­ate professor in the Translational Tumor Immunology pro­gram at The Wistar Institute and senior author of the study. “We wanted to determine why STING agonists behave dif­fer­en­tly in normal and malig­nant B cells and how to extend this cytotoxic activity in malig­nant B cell leukemia, lym­phoma and multiple myeloma.”

Hu and his colleagues focused their attention on the IRE-1/XBP-1 stress response path­way found in the endoplasmic reticulum. This path­way must be activated for STING to function properly in non-B cells. If cells are deficient in either IRE-1 or XBP-1, the cells cannot produce interferons as a response to STING agonists. Additionally, B-cell leukemia, lym­phoma, and myeloma require the IRE-1/XBP-1 path­way to be activated for survival. Results showed the activation of this path­way reduces the level of apop­tosis, suggesting that lower­ing activity of this path­way is important in promoting death of malig­nant B cells. Interestingly, stimulation by STING agonists also suppresses the IRE-1/XBP-1 path­way, which in­­creases the level of apop­tosis in malig­nant B cells. The team further 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, M.D., Ph.D., a postdoctoral fellow in the laboratory of Dr. Hu and first author of the study. “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 co-development partner for the ad­vance­ment of novel STING agonists in treating B-cell hema­to­logic malig­nancies.

This work was sup­ported by the National Institutes of Health grant R01CA163910. Co-authors of this study from The Wistar Institute in­clude Joseph Zundell, Cindy Lin, and Yulia Nefedova. Other co-authors in­clude Sujeewa Ranatunga and Juan Del Valle from the University of South Florida in Tampa.

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The Wistar Institute is an inter­na­tional leader in biomedical research with special expertise in cancer research and vaccine devel­op­ment. Founded in 1892 as the first independent nonprofit biomedical research institute in the country, Wistar has held the prestigious Cancer Center desig­na­tion from the National Cancer Institute since 1972. The Institute works actively to ensure that research ad­vances move from the laboratory to the clinic as quickly as possible. wistar.org.

Source: The Wistar Institute.

Reference:

CA Tang, JA Zundell, et al, "Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells," Cancer Research, published online March 10, 2016 (abstract ^[1], full text of article ^[2] [PDF]).