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Immunotherapy for lung cancer combining the oligodeoxynucleotides of TLR9 agonist and TGF-β2 inhibitor

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Abstract

Tumor immunotherapies have shown promising antitumor effects, especially immune checkpoint inhibitors (ICIs). However, only 12.46% of the patients benefit from the ICIs, the rest of them shows limited effects on ICIs or even accelerates the tumor progression due to the lack of the immune cell infiltration and activation in the tumor microenvironment (TME). In this study, we administrated a combination of Toll-like receptor 9 (TLR9) agonist CpG ODN and Transforming growth factor-β2 (TGF-β2) antisense oligodeoxynucleotide TIO3 to mice intraperitoneally once every other day for a total of four injections, and the first injection was 24 h after LLC cell inoculation. We found that the combination induced the formation of TME toward the enrichment and activation of CD8+ T cells and NK cells, accompanied with a marked decrease of TGF-β2. The combined therapy also effectively inhibited the tumor growth and prolonged the survival of the mice, even protected the tumor-free mice from the tumor re-challenge. Both of CpG ODN and TIO3 are indispensable, because replacing CpG ODN with TLR9 inhibitor CCT ODN showed no antitumor effect, CpG ODN or TIO3 alone did not lead to ideal antitumor results. This effect was possibly initiated by the activation of dendritic cells at the tumor site. This systemic antitumor immunotherapy with a combination of the two oligonucleotides (an immune stimulant and an immunosuppressive cytokine inhibitor) before the tumor formation may provide a novel strategy for clinical prevention of the postoperative tumor recurrence.

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Acknowledgements

The authors would like to thank Lin Lv and Brandon Smith for polishing the English of the whole manuscript; Peiyan Zhao, Shengnan Wang, Mengru Zhu, Feiyu Lu, Mengyuan Kou, Yangyang Wang, Baichao Sun and Zhengyi Sun for technical assistance; Lei Zhou for her support in the use of confocal microscopy. This work was supported by the National Nature Science Foundation of China (8147888).

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  1. Department of Molecular Biology in College of Basic Medical Sciences and Institute of Pediatrics in The First Hospital of Jilin University, Jilin University, Changchun, 130021, Jilin, People’s Republic of China

    Yunpeng Yao, Jianhua Li, Yangeng Wang, Wenting Lu & Liying Wang

  2. Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin, People’s Republic of China

    Kuo Qu, Zhe Wang & Yongli Yu

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  1. Yunpeng Yao
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YY (Yunpeng Yao) was the main researcher for this study including the experiment design and operation, data analysis, and manuscript writing; JL, KQ, ZW, and YW participated in operation for some experiments including flow cytometry, and mouse experiments. WL provided writing of the manuscript. YY (Yongli Yu) and LW provided research ideas and funds and involved in writing and revising of the manuscript.

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Yao, Y., Li, J., Qu, K. et al. Immunotherapy for lung cancer combining the oligodeoxynucleotides of TLR9 agonist and TGF-β2 inhibitor. Cancer Immunol Immunother 72, 1103–1120 (2023). https://doi.org/10.1007/s00262-022-03315-0

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