TAKAHAMA, Shokichi; ISHIGE, Kazuya; NOGIMORI, Takuto; YASUTOMI, Yasuhiro; APPAY, Victor; YAMAMOTO, Takuya

doi:10.1016/j.omtm.2022.12.008

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Article de revue

Ce document a été publié dans

Molecular Therapy Methods and Clinical Development. 2023, vol. 28, p. 99-115

Résumé en anglais

Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not been reported. We examined the effects of escalating doses of cyclic-di-adenosine monophosphate (c-di-AMP) or cyclic [G (3′,5′)pA (3′,5′p] (3′-3′-cGAMP) administered intramuscularly or intravenously to cynomolgus macaques. Both ligands induced transient local and systemic inflammatory responses and systemic immunomodulatory responses, including the upregulation of interferon-α (IFN-α) and IFN-γ expression and the activation of multiple immunocompetent cell subsets. Better immunological responses were observed in animals that received c-di-AMP compared with those that received 3′-3′-cGAMP. Multi-parameter analysis using a dataset obtained before administering the ligands predicted the efficacy outcome partially. Importantly, the efficacy of these ligands was reduced in older macaques. We propose that 0.5 mg/kg c-di-AMP via intramuscular administration should be the optimal starting point for clinical studies. Our study is the first to demonstrate the age-dependent safety and efficacy of STING-L in non-human primates and supports the potential of STING-L use as a direct immunomodulator in vivo. © 2022 The Author(s)< Réduire

Mots clés en anglais

STING ligands

Non-human primate

Aging

Flow cytometry

Innate immunity

Prediction

URI

https://oskar-bordeaux.fr/handle/20.500.12278/201348

DOI

http://dx.doi.org/10.1016/j.omtm.2022.12.008

Unités de recherche

ImmunoConcEpT - UMR 5164

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Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates

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