LIFE SCIENCE

Scientists have discovered novel immune escape mechanisms for the STING pathway


Recently, the Jenny P.Y. Ting team at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill in the United States collaborated with the Yuliya Pylayeva-Gupta lab to reveal for the first time the novel immune escape mechanism of the STING pathway. The study was published online in the journal Nature on October 5.

In recent years, immunotherapy has revolutionized the field of cancer treatment, but there is still a considerable number of patients who do not respond to immunotherapy. In cold tumors or solid tumors, the pre-existing anti-tumor immune population is insufficient, which is an important obstacle to the response of immunotherapy treatment.

The cGAS/STING pathway is one of the most important ways to identify molecules associated with radiation therapy, damage generated during chemotherapy, and abnormal DNA within cells. Preclinical studies have shown that STING signal activation activates the immune response of anti-tumor killer cells and promotes the expression of a large number of cytokines, chemokines and interferons type 1. Therefore, STING agonists are widely used in the research and development of new antitumor drugs.

However, clinical trials have shown no significant benefit from STING agonists alone. When blocking antibodies that bind to PDL1 or PD1 at T cell immune checkpoints, the antitumor effect yielded little effect. To date, clinically applicable STING agonists have not been successfully developed, and the mechanism of resistance of tumor patients to STING agonist immunotherapy is not clear and needs to be further elucidated.

“Through the analysis of the immune cell class in the tumor, we found that the systematic delivery of STING agonists can accumulate a large number of regulatory B cells locally in solid tumors, and through genetic deprivation, unbiased sequencing, antibody blockade and other demonstration methods, we proved that STING agonists can promote the local expansion of inhibitory IL-35+ B cells in tumors, ultimately hindering the proliferation of NK effector cells and weakening the latter’s anti-tumor immune response.” Co-first author of this paper, Li Sirui, a postdoctoral fellow at the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, introduced it.

Fig. 1.jpg

Study schematic diagram from the paper

She told China Science Daily that “the combination of STING agonists and inhibitory cytokine IL-35 blocking antibodies as cancer immunotherapy provides a new idea for the combination therapy based on STING agonists, which is expected to bring good news to tumor patients.” (Source: China Science Daily Liu Runan)

Related Paper Information:https://doi.org/10.1038/s41586-022-05254-3



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