STING agonist and IDO inhibitor combination therapy inhibits tumor progression in murine models of colorectal cancer

Shi, Jiaqi; Liu, Caiqi; Luo, Sai; Cao, Tingyu; Lin, Binlin; Zhou, Meng; Zhang, Xiao; Wang, Song; Zheng, Tongsen; Li, Xiaobo

doi:10.1016/j.cellimm.2021.104384

Cited by 33 publications

(21 citation statements)

References 54 publications

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“…Local injection of STING ligands can repolarize macrophages 47 and is effective in murine tumor models also in various combination protocols. 64 , 65 Given that such studies are on-going in patients with various tumors, 66 , 67 the potential activation of intratumoral γδ T cells by local application of STING ligands is of great interest and needs to be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

et al. 2022

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Ligands for Stimulator of Interferon Genes (STING) receptor are under investigation as adjuvants in cancer therapy. Multiple effects have been described, including induction of immunogenic cell death and enhancement of CD8 T-cell mediated anti-tumor immunity. However, the potential effects of STING ligands on activation and effector functions of tumor-reactive human γδ T cells have not yet been investigated. We observed that cyclic dinucleotide as well as novel non-dinucleotide STING ligands diABZI and MSA-2 co-stimulated cytokine induction in Vδ2 T cells within peripheral blood mononuclear cells but simultaneously inhibited their proliferative expansion in response to the aminobisphosphonate Zoledronate and to γδ T-cell specific phosphoantigen. In purified γδ T cells, STING ligands co-stimulated cytokine induction but required the presence of monocytes. STING ligands strongly stimulated IL-1β and TNF-α secretion in monocytes and co-stimulated cytokine induction in short-term expanded Vδ2 γδ T-cell lines. Simultaneously, massive cell death was triggered in both cell populations. Activation of STING as revealed by TBK1/IRF3 phosphorylation and IP-10 secretion varied among STING-expressing tumor cells. STING ligands modulated tumor cell killing by Vδ2 T cells as analyzed in Real-Time Cell Analyzer to variable degree, depending on the tumor target and time course kinetics. Our study reveals complex regulatory effects of STING ligands on human γδ T cells in vitro . These results help to define conditions where STING ligands might boost the efficacy of γδ T cell immunotherapy in vivo .

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Section: Discussionmentioning

confidence: 99%

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

et al. 2022

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“…STING agonist diABZI combined with an inhibitor of indoleamine 2,3-dioxygenase (IDO), an enzyme which can inhibit T cell proliferation and mediate cancer immune evasion, suppressed colorectal cancer growth and prolonged the survival time of colorectal cancer mice. 123 Interestingly, the gut microbiota is emerging as an indispensable factor for cancer immunotherapy. 124 Recently, it is shown that cGAS-STING signaling pathway is involved in microbiota-facilitated immunotherapy.…”

Section: Targeting Cgas-sting Signaling Pathway In Colorectal Cancermentioning

confidence: 99%

“…Apart from ICBs, synergistic antitumor effects of the combination of STING agonist with other immunotherapy drugs were also observed. STING agonist diABZI combined with an inhibitor of indoleamine 2,3‐dioxygenase (IDO), an enzyme which can inhibit T cell proliferation and mediate cancer immune evasion, suppressed colorectal cancer growth and prolonged the survival time of colorectal cancer mice 123 . Interestingly, the gut microbiota is emerging as an indispensable factor for cancer immunotherapy 124 .…”

Section: Targeting the Cgas–sting Signaling Pathway For Treatment Of ...mentioning

confidence: 99%

cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

Jiang

2021

The FASEB Journal

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Cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has emerged as a key DNA-sensing machinery in innate immunity. Activation of cGAS-STING signaling pathway mediates the production of interferons and proinflammatory cytokines. Although cGAS-STING signaling pathway shows critical function in the maintenance of gut homeostasis, overactive cGAS-STING signaling pathway leads to gastrointestinal (GI) inflammation.Harnessing the effect and mechanism of the cGAS-STING signaling pathway could be beneficial for the development of novel strategies for the treatment of GI diseases. This review presents recent advances regarding the role of cGAS-STING signaling pathway in GI inflammatory disease and cancers and describes perspective therapeutic strategies targeting the signaling pathway.

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“…It is worth noting that the proteolysis targeting chimera (PROTAC) technique has been used to degrade IDO1 as a strategy for cancer immunotherapy ( Hu et al, 2020 ). In regard to these inhibitors, it has been proven that IDO1 inhibitors, such as 1-methyltryptophan (1-MT) and epigallocatechin gallate, can act synergistically with immune checkpoint inhibitors to enhance their antitumor efficacy in CRC ( Shi et al, 2021 ). However, tumor cells and myeloid cells may express tryptophan 2,3-dioxygenase 2 (TDO2) and catabolize tryptophan via an alternative pathway that replaces or complements IDO1.…”

Section: Introductionmentioning

confidence: 99%

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice

et al. 2022

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Although the antitumor efficacy of immune checkpoint blockade (ICB) has been proved in colorectal cancer (CRC), the results are unsatisfactory, presumably owing to the presence of tryptophan metabolism enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2). However, only a few dual inhibitors for IDO1 and TDO2 have been reported. Here, we discovered that sodium tanshinone IIA sulfonate (STS), a sulfonate derived from tanshinone IIA (TSN), reduced the enzymatic activities of IDO1 and TDO2 with a half inhibitory concentration (IC50) of less than 10 μM using enzymatic assays for natural product screening. In IDO1- or TDO2- overexpressing cell lines, STS decreased kynurenine (kyn) synthesis. STS also reduced the percentage of forkhead box P3 (FOXP3) T cells in lymphocytes from the mouse spleen cocultured with CT26. In vivo, STS suppressed tumor growth and enhanced the antitumor effect of the programmed cell death 1 (PD1) antibody. Compared with anti-PD1 (α-PD1) monotherapy, combined with STS had lower level of plasma kynurenine. Immunofluorescence assay suggested that STS decreased the number of FOXP3+ T cells and increased the number of CD8+ T cells in tumors. Flow cytometry analysis of immune cells in tumor tissues demonstrated an increase in the percentage of tumor-infiltrating CD8+ T cells. According to our findings, STS acts as an immunotherapy agent in CRC by inhibiting both IDO1 and TDO2.

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STING agonist and IDO inhibitor combination therapy inhibits tumor progression in murine models of colorectal cancer

Cited by 33 publications

References 54 publications

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

cGAS–STING signaling pathway in gastrointestinal inflammatory disease and cancers

Sodium Tanshinone IIA Sulfonate as a Potent IDO1/TDO2 Dual Inhibitor Enhances Anti-PD1 Therapy for Colorectal Cancer in Mice

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