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Combination of IFN-gamma with STING agonist and PD-1 immune checkpoint blockade: a potential immunotherapy for gastric cancer

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Abstract

Suppression of the cGAS-STING pathway is an immune escape mechanism in cancer cells. The critical role of this pathway in gastric cancer (GC) is not fully understood. Herein, we evaluated the effect of the interferon-gamma (IFN-gamma), STING agonist, PD-1 immune checkpoint blockade, and their combination on the cGAS-STING pathway in GC. Expression of cGAS and STING in tumor tissue samples and adjacent normal tissue (ANT) biopsies of fifty new GC patients was evaluated by quantitative real-time PCR (qRT-PCR). Moreover, cGAS and STING expression levels were examined in Peripheral Blood Mononuclear Cells (PBMC) samples of forty GC patients and twenty-five healthy subjects. The apoptosis rate of cancer cells was analyzed by Annexin V-FITC/PI. Cell proliferation was measured by the BrdU assay. Also, IFN-β levels were evaluated in the supernatants of the treated groups. The cGAS expression was decreased in patients with distant metastasis. Co-cultures treated with IFN-gamma showed an elevated level of cGAS and STING expressions in PBMC and cancer cells. The rate of apoptosis increased in all the treatment groups. In addition, the rate of proliferation in PBMCs increased in different treated groups. The main role of PBMCs in cytotoxicity was determined by a comparative analysis of the viability of cells treated with all treatments, both with and without PBMCs. The production of IFN-β was elevated in all treated groups. The current study suggests that a combination therapy using IFN-gamma, STING agonist, and anti-PD-1 antibody can provide a promising approach to the treatment of GC.

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Data availability

Data are available upon request of the authors. The authors declare that the material is original, has not been published before, nor is under consideration in any other journal.

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Acknowledgements

This study was supported by the Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Mazandaran.

Funding

The authors would like to appreciate Digestive Disease Research Center, Ardabil University of Medical Sciences, for financially supporting this project (1003253).

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Authors and Affiliations

  1. Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran

    Shahnaz Hosseinzadeh & Elham Safarzadeh

  2. Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Shahnaz Hosseinzadeh, Narjes Jafari & Saeid AbedianKenari

  3. Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran

    Mahsa Imani

  4. Digestive Disease Research Center, Ardabil University of Medical Sciences, Ardabil, Iran

    Farhad Pourfarzi

  5. Department of Immunology, Faculty of Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, 4816978741, Mazandaran, Iran

    Saeid AbedianKenari

  6. Department of Microbiology, Parasitology and Immunology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, 5166614711, Iran

    Elham Safarzadeh

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  1. Shahnaz Hosseinzadeh
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  2. Mahsa Imani
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Contributions

SH: conceptualization, investigation, methodology, project administration, writing original draft; MI: methodology and writing original draft; FP: resources, funding acquisition; NJ: writing original draft; SAK: supervision, methodology, visualization, funding acquisition; ES: supervision, visualization, methodology, data curation.

Corresponding authors

Correspondence to Saeid AbedianKenari or Elham Safarzadeh.

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Conflict of interests

Shahnaz Hosseinzadeh, Mahsa Imani, Farhad Pourfarzi, Narjes Jafari, Saeid AbedianKenari, and Elham Safarzadeh declare that they have no conflict of interest that might be relevant to the contents of this manuscript.

Ethical approval

The study entitled Combination of IFN-gamma with STING agonist and PD-1 immune checkpoint blockade: A Potential Immunotherapy for Gastric Cancer was approved by the Research Ethics Committee of Mazandaran University of Medical Sciences (IR.MAZUMS.REC.1398.1295), Sari, Iran, in accordance with the guidelines.

Consent to participate

Informed consent was obtained in accordance with the principles of the revised Declaration of Helsinki and approved by the Research Ethics Committee of Mazandaran University of Medical Sciences (IR.MAZUMS.REC.1398.1295) in Sari, Iran.

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Hosseinzadeh, S., Imani, M., Pourfarzi, F. et al. Combination of IFN-gamma with STING agonist and PD-1 immune checkpoint blockade: a potential immunotherapy for gastric cancer. Med Oncol 41, 110 (2024). https://doi.org/10.1007/s12032-024-02326-4

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