STING Agonists Induce Regulatory B-cell Expansion and Diminished NK-cell Function

Preclinical studies have indicated that use of cGAS–STING pathway agonists can overcome immunosuppression in tumors. However, the use of STING agonists in clinical trials reveals tumor resistance, and the mechanisms that underlie this poor efficacy have not yet been fully elucidated. To investigate potential mechanisms behind the poor clinical response of STING monotherapy, Li, Mirlekar, and colleagues used five distinct STING agonists, including cGAMP, in murine models of pancreatic cancer and showed expansion of intratumoral regulatory B cells. Systemic cGAMP treatment alone was found not to alter tumor growth but did lead to the induction of mRNA necessary for the expression of the immunosuppressive cytokines IL10 and IL35. Additional characterization of the STING pathways that support IL35 and IL10 expression indicates that their upregulation is mediated through an interferon-independent but STING–IRF3-dependent mechanism. Notably, loss of STING in B cells or cGAMP treatment in B cell–deficient mice reduced tumor growth in multiple murine tumor models as well as increased intratumoral natural killer (NK) cells, whereas B cell–specific IL35 expression in the tumor led to decreased NK-cell frequency. Moreover, combining cGAMP with IL35 or neutralizing antibody treatment demonstrated that the anti-IL35 and cCAMP combination reduced tumor burden most effectively as well as prolonged survival and significantly increased infiltrating NK cells. Furthermore, depletion experiments demonstrated that loss of NK cells abrogated this observed tumor reduction, suggesting that NK cells are mediators of the antitumor effect. The link between STING and immunosuppressive cytokines was also evaluated in samples from patients with pancreatic cancer, and similar trends to murine models were observed, supporting the occurrence of these effects in humans. In summary, the results of this study demonstrate a potential mechanism behind the poor clinical effects of STING agonists that involves immunosuppressive B cells and their inhibition of NK cells and suggest the blockage of this circuit as a potential strategy to aid in tumor control.

Li S, Mirlekar B, Johnson BM, Brickey WJ, Wrobel JA, Yang N, et al. STING-induced regulatory B cells compromise NK function in cancer immunity. Nature 2022;610:373–80.

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