SHR1032, a novel STING agonist, stimulates anti-tumor immunity and directly induces AML apoptosis.

Abstract

Stimulator of interferon genes (STING) activation induces type I interferons and pro-inflammatory cytokines which stimulate tumor antigen cross presentation and the adaptive immune responses against tumor. The first-generation of STING agonists, cyclic di-nucleotide (CDN), mimicked the endogenous STING ligand cyclic guanosine monophosphate adenosine monophosphate, and displayed limited clinical efficacy. Here we report the discovery of SHR1032, a novel small molecule non-CDN STING agonist. Compared to the clinical CDN STING agonist ADU-S100, SHR1032 has much higher activity in human cells with different STING haplotypes and robustly induces interferon β (IFNβ) production. When dosed intratumorally, SHR1032 induced strong anti-tumor effects in the MC38 murine syngeneic tumor model. Pharmacodynamic studies showed induction of IFNβ, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) in the tumors and, to a lower extent, in the plasma. More importantly, we found SHR1032 directly causes cell death in acute myeloid leukemia (AML) cells. In conclusion, our findings demonstrate that in addition to their established ability to boost anti-tumor immune responses, STING agonists can directly eradicate AML cells, and SHR1032 may present a new and promising therapeutic agent for cancer patients.

• Authors: Chunying Song, Dong Liu, Suxing Liu, Di Li, Ivana Horecny, Xinzhu Zhang, Puhui Li, Lei Chen, Matthew Miller, Rasheduzzaman Chowdhury, Mena Issa, Ru Shen, Yinfa Yan, Fengqi Zhang, Lei Zhang, Limin Zhang, Chang Bai, Jun Feng, Linghang Zhuang, Rumin Zhang, Jing Li, Hilary Wilkinson, Jian Liu, Weikang Tao
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 8579 (05 20 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 35595822 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Cytokines
• Membrane Proteins
• Sting1 protein, mouse
• Interferon-beta

Topics

• Animals
• Apoptosis
• Cytokines (metabolism)
• Humans
• Immunotherapy
• Interferon-beta (metabolism)
• Leukemia, Myeloid, Acute (drug therapy)
• Membrane Proteins (agonists, metabolism)
• Mice