STING-induced regulatory B cells compromise NK function in cancer immunity
Autor: | 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 |
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Rok vydání: | 2022 |
Předmět: | |
Zdroj: | Nature |
ISSN: | 1476-4687 0028-0836 |
Popis: | An immunosuppressive tumour microenvironment is a major obstacle in the control of pancreatic and other solid cancers(1–3). Agonists of the stimulator of interferon genes (STING) protein trigger inflammatory innate immune responses to potentially overcome tumour immunosuppression(4). Although these agonists hold promise as potential cancer therapies(5), tumour resistance to STING monotherapy has emerged in clinical trials and the mechanism(s) are unclear(5–7). 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 lymphocytes 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. |
Databáze: | OpenAIRE |
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