Journal Article

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

Mirlekar, Bhalchandra, Entwistle, Sarah, Li, Sirui, Johnson, Brandon M., Song, Dingka, Pylayeva-Gupta, Yuliya, Li, Wei, Wrobel, John A., Brickey, W. June, Yang, Na, Tan, Xianming, Gale, Michael, Ting, Jenny P.-Y., Cui, Ya, Vincent, Benjamin G., Deng, Meng

2022

Overview

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 g enes (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) is 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 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. Systemic treatment of pancreatic cancer with STING agonist stimulates regulatory B cells to express immunosuppressive cytokine IL-35, which weakens the anti-tumour function of natural killer cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/21 / 13/31 / 13/51 / 14/63 / 45/91 / 631/250/251 / 631/67/580 / Ablation / Agonists / Animals / Antigens / B-Lymphocytes, Regulatory - immunology / Beta cells / Cancer / Cell proliferation / Clinical trials / Combinatorial analysis / Cytokines / Flow cytometry / Genes / Grants / Humanities and Social Sciences / Humans / Immunity, Innate - immunology / Immunosuppression / Immunotherapy / Inflammation / Innate immunity / Interferon / Interferon Regulatory Factor-3 / Interferon Type I - immunology / Interleukins / Interleukins - antagonists & inhibitors / Killer Cells, Natural - immunology / Medical research / Membrane Proteins - agonists / Membrane Proteins - metabolism / Mice / Microenvironments / multidisciplinary / Natural killer cells / Neoplasms - drug therapy / Neoplasms - immunology / Nucleotides, Cyclic - metabolism / Pancreatic cancer / Science / Science (multidisciplinary) / Stimulators / Tumor Microenvironment / Tumors