STING-induced regulatory B cells compromise NK function in cancer immunity

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 () and Jenny P.-Y. Ting ()
Additional contact information
Sirui Li: University of North Carolina at Chapel Hill
Bhalchandra Mirlekar: University of North Carolina at Chapel Hill
Brandon M. Johnson: University of North Carolina at Chapel Hill
W. June Brickey: University of North Carolina at Chapel Hill
John A. Wrobel: University of North Carolina at Chapel Hill
Na Yang: Functional Epigenomics Unit (HNN-2G5), National Institute on Aging
Dingka Song: University of North Carolina at Chapel Hill
Sarah Entwistle: University of North Carolina at Chapel Hill
Xianming Tan: University of North Carolina at Chapel Hill
Meng Deng: University of North Carolina at Chapel Hill
Ya Cui: Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine
Wei Li: Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine
Benjamin G. Vincent: University of North Carolina at Chapel Hill
Michael Gale: University of Washington
Yuliya Pylayeva-Gupta: University of North Carolina at Chapel Hill
Jenny P.-Y. Ting: University of North Carolina at Chapel Hill

Nature, 2022, vol. 610, issue 7931, 373-380

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41586-022-05254-3

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