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

Menée à l'aide de lignées cellulaires et de modèles murins de tumeurs, cette étude met en évidence un mécanisme par lequel les agonistes de la protéines STING, en favorisant l'expression de l'interleukine IL-35 par les lymphocytes B, réduisent la prolifération des cellules NK et atténuent la réponse antitumorale induite par ces cellules

Résumé en anglais

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.