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Reovirus combined with a STING agonist enhances anti-tumor immunity in a mouse model of colorectal cancer

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Abstract

Reovirus, a naturally occurring oncolytic virus, initiates the lysis of tumor cells while simultaneously releasing tumor antigens or proapoptotic cytokines in the tumor microenvironment to augment anticancer immunity. However, reovirus has developed a strategy to evade antiviral immunity via its inhibitory effect on interferon production, which negatively affects the induction of antitumor immune responses. The mammalian adaptor protein Stimulator of Interferon Genes (STING) was identified as a key regulator that orchestrates immune responses by sensing cytosolic DNA derived from pathogens or tumors, resulting in the production of type I interferon. Recent studies reported the role of STING in innate immune responses to RNA viruses leading to the restriction of RNA virus replication. In the current study, we found that reovirus had a reciprocal reaction with a STING agonist regarding type I interferon responses in vitro; however, we found that the combination of reovirus and STING agonist enhanced anti-tumor immunity by enhancing cytotoxic T cell trafficking into tumors, leading to significant tumor regression and survival benefit in a syngeneic colorectal cancer model. Our data indicate the combination of reovirus and a STING agonist to enhance inflammation in the tumor microenvironment might be a strategy to improve oncolytic reovirus immunotherapy.

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Data availability statement

The data supporting this study's findings are available from the corresponding author (E.K.) upon reasonable request.

Abbreviations

CRC:

Colorectal cancer

cGAMP:

Cyclic GMP-AMP

cGAS:

Cyclic GMP-AMP synthase

dsDNA:

Double-stranded DNA

FACS:

Fluorescence-activated cell sorting

iNOS:

Inducible nitric oxide synthesis

IFN:

Interferon

IT:

Intratumoral

MOI:

Multiplicity of infection

MSI:

Microsatellite instability

pfu:

Plaque-forming units

PBS:

Phosphate buffered saline

PD-1:

Programmed cell death 1

PD-L1:

Programmed cell death ligand 1

RT-PCR:

Reverse transcription–polymerase chain reaction

STING:

Stimulator of Interferon Genes

TAMs:

Tumor-associated macrophages

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Acknowledgements

We would like to thank Mrs. Yukimi Ito from Nagoya City University for her technical assistance. We thank J. Ludovic Croxford, PhD, from Edanz Group (https://en-author-services.edanzgroup.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by Grants-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS), KAKENHI Grant Number 18K07951and 22K16002.

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Authors and Affiliations

  1. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Mizuho-Ku, Nagoya, 467-8601, Japan

    Naomi Sugimura, Eiji Kubota, Mamoru Tanaka, Takaya Shimura & Hiromi Kataoka

  2. Department of Gastroenterology, Nagoya City University West Medical Center, Kita-Ku, Nagoya, 462-8508, Japan

    Yoshinori Mori

  3. Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Mizuho-Ku, Nagoya, 467-8603, Japan

    Mineyoshi Aoyama

  4. Department of Gastroenterology, Gamagori Municipal Hospital, Hirata-Cho, Gamagori, 443-8501, Japan

    Satoshi Tanida

  5. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB, T2N 4N1, Canada

    Randal N. Johnston

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  1. Naomi Sugimura
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  2. Eiji Kubota
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  3. Yoshinori Mori
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Contributions

SN, EK, YM, and HK were involved with the conception and performance of experiments, statistical analysis, and writing the manuscript. MT, TS, and ST assisted with some of the experiments. RNJ and MA were involved with the conception and design of experiments. All authors reviewed and edited the manuscript.

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Correspondence to Eiji Kubota.

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Sugimura, N., Kubota, E., Mori, Y. et al. Reovirus combined with a STING agonist enhances anti-tumor immunity in a mouse model of colorectal cancer. Cancer Immunol Immunother 72, 3593–3608 (2023). https://doi.org/10.1007/s00262-023-03509-0

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