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Unexpected Breg-NK crosstalk in STING agonist therapy

Cellular & Molecular Immunology volume 19, pages 1330–1332 (2022)Cite this article

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The cyclic GMP-AMP synthase (cGAS)-STING pathway is a critical double-stranded DNA (dsDNA) sensor that detects a broad DNA repertoire of antigens, both of foreign and self-origin, that enables immune responses independent of pathogen-specific attributes [4]. Activated cGAS triggers oligomerization and endoplasmic reticulum (ER)-Golgi trafficking of the STING protein and leads to interferon regulatory Factor 3 (IRF3) translocation to the nucleus, consequently inducing type I interferon expression [4]. Previous studies have identified STING signaling as an initial event in the priming of CD8+ T cells against tumor-associated antigens, which has led to great interest in using STING agonists as novel cancer therapeutics to enhance antitumor T-cell responses [5, 6]. Multiple STING agonists have been widely explored for cancer immunotherapy and have achieved tremendous progress in preclinical work in diverse solid tumors. However, few, if any, have shown meaningful efficacy in large-scale clinical trials even in combination with immune checkpoint blockade therapy [7]. Here, the authors posit that STING-induced IL-35+ Breg cells inhibit NK-mediated tumor cytotoxicity, which could be a major component of the failure of STING agonists in clinical trials.

To examine the effect of systemic application of the STING agonist cGAMP in pancreatic ductal adenocarcinoma (PDAC), Li et al. injected cGAMP intravenously into orthotopic KPC4662 tumor-bearing mice and found no benefit in terms of tumor reduction but did find that it dramatically increased the proportion of intratumoral CD19+ B cells. B-cell-specific deletion of STING universally reduced tumor burden in models of PDAC, breast cancer, lung cancer and melanoma, indicating that the activation of the STING pathway in B cells is protumorigenic. In contrast, T-cell-specific deletion of STING accelerated tumor growth. RNA sequencing (RNA-Seq) analysis showed that Il10 and Ebi3 were upregulated in cGAMP-treated WT B cells, which hinted at the involvement of the immunosuppressive cytokines IL-10 and IL-35. As expected, they confirmed that five STING agonists, including cGAMP, all significantly induced IL-10 and IL-35 production in B cells and did not reduce the tumor burden. These B cells showed a CD1dhiCD5+CD21hi Breg phenotype. Using a cell tracing system, the authors found that those tumor-infiltrating IL-35+ Bregs originated from the spleen.

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Acknowledgements

This work was supported by the NIH R01CA213990 and R01AI128818 (J.Y.). The figure was created with BioRender.com.

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Authors and Affiliations

  1. Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA

    Yunke Wang, Anne E. Geller & Jun Yan

  2. Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA

    Anne E. Geller & Jun Yan

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  1. Yunke Wang
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  2. Anne E. Geller
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YW, AG, and JY conceptualized the study. YW drafted the manuscript. YW, AG, and JY contributed to manuscript editing and revision.

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Correspondence to Jun Yan.

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Wang, Y., Geller, A.E. & Yan, J. Unexpected Breg-NK crosstalk in STING agonist therapy. Cell Mol Immunol 19, 1330–1332 (2022). https://doi.org/10.1038/s41423-022-00952-4

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