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Improvement of STING-mediated cancer immunotherapy using immune checkpoint inhibitors as a game-changer

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Abstract

Various cancer therapies, such as surgery, radiotherapy, chemotherapy, and immunotherapy, have been used to treat cancer. Among cancer immunotherapies, stimulators of interferon genes (STING) activate various immune cells and induce them to attack cancer cells. However, the secretion of type I interferon (IFN α and β) increases after stimulation of the immune cell as a side effect of STING agonist, thereby increasing the expression of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Therefore, it is necessary to reduce the side effects of STING agonists and maximize cancer treatment by administering combination therapy. Tumor-bearing mice were treated with cisplatin, tumor-specific peptide, neoantigen, DMXAA (STING agonist), and immune checkpoint inhibitor (ICI). The combination vaccine group showed a reduction in tumor mass, an increased survival rate, and IFN-γ+ (interferon gamma) CD8+ (cluster of differentiation 8) T cells in the spleen and TME. The distribution of immune cells in the spleen and TME was confirmed, and the number of active immune cells increased, whereas that of immunosuppressive cells decreased. When measuring cytokine levels in the tumor and serum, the levels of pro-inflammatory cytokines increased and anti-inflammatory cytokines decreased. This study demonstrated that when various cancer therapies are combined to treat cancer, it can lead to an anticancer immune synergistic effect by increasing the immune response and reducing side effects.

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Availability of data and material

The datasets analyzed in the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

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Funding

This study was supported by National Research Foundation of Korea (NRF) Grants funded by the Korean government (NRF-2016R1A5A2012284 and NRF-2018R1A2B6008455).

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Authors and Affiliations

  1. Department of Immunology, College of Medicine, Konkuk University, 268 Chungwon-daero, Chungju-si, Chungcheongbuk-do, 27478, South Korea

    Sung Eun Lee, Gun-Young Jang, Ji won Lee, Sang Hyeon Park, Hee Dong Han & Yeong-Min Park

  2. Innovative Discovery Center, Prestigebiopharma Korea, Myeongjigukje 7-ro, 44, Gangseo-gu, Busan, South Korea

    Tae Heung Kang

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  1. Sung Eun Lee
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Contributions

SEL, GYJ, HDH, YMP, and THK designed experiments. SEL, GYJ, JWL, and SHP conducted experiments. SEL and THK analyzed the data and wrote the manuscript. HDH verified the statistical methods used. All the authors provided critical feedback and contributed to the final manuscript. THK supervised this project.

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Correspondence to Yeong-Min Park or Tae Heung Kang.

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In the name of all the authors, I gave my full consent to participate.

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I have given my full consent for publication in the name of all authors.

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All animal experiments were approved by the Konkuk University Institutional Animal Care Use Committee (IACUC, KU20104).

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Lee, S.E., Jang, GY., Lee, J.w. et al. Improvement of STING-mediated cancer immunotherapy using immune checkpoint inhibitors as a game-changer. Cancer Immunol Immunother 71, 3029–3042 (2022). https://doi.org/10.1007/s00262-022-03220-6

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