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

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

doi:10.1038/s41586-022-05254-3

Cited by 147 publications

(110 citation statements)

References 63 publications

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“…Interestingly, in a positive-feedback loop, IL-35 is shown to drive the development of conventional B cells and IL-10producing B cells (also termed B10 cells) into B reg cells. 16 In line with these data, Li et al 4 1).…”

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confidence: 69%

“…This interesting new work by Li et al 4 identifies that STING activation within immature B cells leads to the development of a subset of B reg cells that dampen NK cell proliferation and cytotoxic activity. 4 Systemic administration of the natural STING agonist, cGAMP, into wildtype mice bearing pancreatic ductal adenocarcinoma (PDAC) tumor increased the percentage of B cells among CD45 + intratumoral cells. This was regardless of the number of total CD45 + cells or tumor size, which was surprisingly unaffected by cGAMP treatment, indicating that systemic administration of cGAMP alone in the PDAC model is insufficient to induce antitumor activity.…”

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confidence: 98%

“…In their recent Nature research article, Li et al shed new light on the use of STING agonists in cancer therapy by identifying a potential mechanism through which STING activation in vivo can actually dampen the antitumor response rather than boost it. 4 Immunotherapies enhance our immune system's capacity to recognize and eliminate cancer cells.…”

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confidence: 99%

“…STING activation has been shown previously to induce several downstream responses including type I IFN response, NF-jB-and MAP kinase-dependent proinflammatory cytokine production, autophagy, cell senescence and various programmedcell death pathways. 1 To understand which aspect of STING signaling within B cells abrogates cGAMPinduced antitumor immunity, Li et al 4 conducted a RNAseq analysis comparing differentially expressed genes between untreated and cGAMP-treated wildtype B cells. Interestingly, interleukin (IL)-10, the cytokine encoded by gene Il10, and Ebi3, a subunit of IL-35 cytokine encoded by gene Ebi3, were upregulated in wildtype B cells following cGAMP treatment.…”

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confidence: 99%

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Removing the B (cell) STING to improve cancer immunotherapy

Venkatraman

Nardo

2022

Immunol Cell Biol

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confidence: 69%

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confidence: 98%

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confidence: 99%

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confidence: 99%

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Removing the B (cell) STING to improve cancer immunotherapy

Venkatraman

Nardo

2022

Immunol Cell Biol

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“…On the other hand, indiscriminate STING hyperactivation in non-cancer cells may yield undesired off-target effects including vasculitides, which may limit the patient tolerability of these agents. Furthermore, recent findings demonstrate that systemic delivery of cyclic dinucleotides, including 2'3' cGAMP, repress anti-tumor immunity due to (IL)-35 + regulatory B cell expansion that restricts NK cell-mediated tumor killing 65 . Our findings suggest that c-Src inhibition could be leveraged to induce endogenous production of 2'3' cGAMP in the tumor microenvironment (TME), which would eliminate the need for systemic treatment while still eliciting anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

The proto-oncogene c-Src phosphorylates cGAS to reduce DNA binding and activation

Dunker

Zaver

Howard

et al. 2022

Preprint

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cGMP-AMP synthase (cGAS) is a DNA sensor and responsible for inducing an anti-tumor immune response. Recent studies reveal cGAS is frequently inhibited in cancer, and therapeutic targets to promote anti-tumor cGAS function remain elusive. c-Src is a proto-oncogene tyrosine kinase and is expressed at elevated levels in numerous cancers. Here, we demonstrate that c-Src expression in tumors from various cancers negatively correlates with innate immune gene expression and patient survival. We determine that c-Src restricts cGAS signaling in human cell lines through c-Src small molecule inhibitors, depletion, and overexpression. cGAS and c-Src interact in cells and in vitro, while c-Src directly inhibits cGAS enzymatic activity and DNA binding in a kinase-dependent manner. c-Src phosphorylates cGAS, and inhibition of cGAS Y248 phosphorylation partially reduces c-Src inhibition. Collectively, our study demonstrates that cGAS anti-tumor signaling is hindered by the proto-oncogene c-Src and describes how cancer-associated proteins can regulate the innate immune system.

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Alendronate Triggered Dual‐Cascade Targeting Prodrug Nanoparticles for Enhanced Tumor Penetration and STING Activation of Osteosarcoma

Shen,

Wang,

Bing

et al. 2023

Adv Funct Materials

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The complex physiological environment in bone tissue poses a challenge to the efficient delivery of chemotherapeutic agents for osteosarcoma (OS) treatment; hence, an efficient drug delivery system designed for OS is highly desired. Herein, alendronate (Ale)‐based cationic platinum prodrug nanoparticles (Ale NP) are developed, which exhibit cascade responsiveness to the OS tumor microenvironment. With Ale triggered bone targeting and charge reversal effects, Ale NP demonstrates superior capacity for achieving deep penetration into dense OS tissues. Furthermore, Ale NP can induce dendritic cell (DC) maturation via activation of the cyclic GMP‐AMP synthase‐stimulator of interferon genes (cGAS‐STING) pathway using platinum drugs. The highly potent phenanthridine (Pt(II)) can be released in the presence of overexpressed glutathione (GSH) in tumor cells, thereby achieving dual‐targeted cascade delivery of cationic platinum drugs in OS. Notably, Ale NP not only effectively eliminates the tumor in the internal region of OS but also acts as a potent STING agonist to effectively reverse the suppressive microenvironment of OS. Overall, Ale‐triggered dual‐cascade targeting prodrug nanoparticles significantly improve drug targeting and penetration in OS, hence paving a promising avenue for the clinical treatment of OS.

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

Cited by 147 publications

References 63 publications

Removing the B (cell) STING to improve cancer immunotherapy

Removing the B (cell) STING to improve cancer immunotherapy

The proto-oncogene c-Src phosphorylates cGAS to reduce DNA binding and activation

Alendronate Triggered Dual‐Cascade Targeting Prodrug Nanoparticles for Enhanced Tumor Penetration and STING Activation of Osteosarcoma

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