刺
干扰素基因刺激剂
癌症研究
生物
干扰素
先天免疫系统
免疫学
免疫系统
内部收益率3
免疫抑制
胰腺癌
癌症
遗传学
工程类
航空航天工程
作者
Sirui Li,Bhalchandra Mirlekar,Brandon M. Johnson,W. June Brickey,John A. Wrobel,Na Yang,Dingka Song,Sarah Entwistle,Xianming Tan,Meng Deng,Ya Cui,Wei Li,Benjamin G. Vincent,Michael Gale,Yuliya Pylayeva-Gupta,Jenny P.-Y. Ting
出处
期刊:Nature
[Springer Nature]
日期:2022-10-05
卷期号:610 (7931): 373-380
被引量:74
标识
DOI:10.1038/s41586-022-05254-3
摘要
An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers1-3. Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression4. Although these agonists hold promise as potential cancer therapies5, tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) is unclear5-7. Here we show that the administration of five distinct STING agonists, including cGAMP, results in an expansion of human and mouse interleukin (IL)-35+ regulatory B cells in pancreatic cancer. Mechanistically, cGAMP drives expression of IL-35 by B cells in an IRF3-dependent but type I interferon-independent manner. In several preclinical cancer models, the loss of STING signalling in B cells increases tumour control. Furthermore, anti-IL-35 blockade or genetic ablation of IL-35 in B cells also reduces tumour growth. Unexpectedly, the STING-IL-35 axis in B cells reduces proliferation of natural killer (NK) cells and attenuates the NK-driven anti-tumour response. These findings reveal an intrinsic barrier to systemic STING agonist monotherapy and provide a combinatorial strategy to overcome immunosuppression in tumours.
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