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Int J Biol Sci 2023; 19(9):2648-2662. doi:10.7150/ijbs.81683 This issue Cite

Research Paper

Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug

Jen-Chih Tseng1, Jing-Xing Yang1, Chia-Yin Lee1,4, Chen-Fu Lo2, Yi-Ling Liu1, Mingzi M. Zhang3, Li-Rung Huang3, Ko-Jiunn Liu4, Chien-Chia Wang5, Chi-Ying F. Huang6, Yi-Ren Hong7, Lun K. Tsou2,✉, Tsung-Hsien Chuang1,5,✉

1. Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
2. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
3. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
4. National Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli 35053, Taiwan.
5. Department of Life Sciences, National Central University, Zhongli District, Taoyuan City 32001, Taiwan.
6. Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan.
7. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.

✉ Corresponding authors: thchuangorg.tw (T.-H. Chuang); kelvintsouedu.tw (L.K. Tsou).

Citation:
Tseng JC, Yang JX, Lee CY, Lo CF, Liu YL, Zhang MM, Huang LR, Liu KJ, Wang CC, Huang CYF, Hong YR, Tsou LK, Chuang TH. Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug. Int J Biol Sci 2023; 19(9):2648-2662. doi:10.7150/ijbs.81683. https://www.ijbs.com/v19p2648.htm
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Abstract

Graphic abstract

Head and neck cancer is a major cancer type, with high motility rates that reduce the quality of life of patients. Herein, we investigated the effectiveness and mechanism of a combination therapy involving TLR9 activator (CpG-2722) and phosphatidylserine (PS)-targeting prodrug of SN38 (BPRDP056) in a syngeneic orthotopic head and neck cancer animal model. The results showed a cooperative antitumor effect of CpG-2722 and BPRDP056 owing to their distinct and complementary antitumor functions. CpG-2722 induced antitumor immune responses, including dendritic cell maturation, cytokine production, and immune cell accumulation in tumors, whereas BPRDP056 directly exerted cytotoxicity toward cancer cells. We also discovered a novel function and mechanism of TLR9 activation, which increased PS exposure on cancer cells, thereby attracting more BPRDP056 to the tumor site for cancer cell killing. Killed cells expose more PS in tumor for BPRDP056 targeting. Tumor antigens released from the dead cells were taken up by antigen-presenting cells, which enhanced the CpG-272-promoted T cell-mediated tumor-killing effect. These form a positive feed-forward antitumor effect between the actions of CpG-2722 and BPRDP056. Thus, the study findings suggest a novel strategy of utilizing the PS-inducing function of TLR9 agonists to develop combinational cancer treatments using PS-targeting drugs.

Keywords: Cancer immunotherapy, CpG-oligodeoxynucleotide, Immunogenic cell death, Phosphatidylserine-targeting prodrug, Toll-like receptor, Topoisomerase I inhibitor

Citation styles

APA
Tseng, J.C., Yang, J.X., Lee, C.Y., Lo, C.F., Liu, Y.L., Zhang, M.M., Huang, L.R., Liu, K.J., Wang, C.C., Huang, C.Y.F., Hong, Y.R., Tsou, L.K., Chuang, T.H. (2023). Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug. International Journal of Biological Sciences, 19(9), 2648-2662. https://doi.org/10.7150/ijbs.81683.

ACS
Tseng, J.C.; Yang, J.X.; Lee, C.Y.; Lo, C.F.; Liu, Y.L.; Zhang, M.M.; Huang, L.R.; Liu, K.J.; Wang, C.C.; Huang, C.Y.F.; Hong, Y.R.; Tsou, L.K.; Chuang, T.H. Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug. Int. J. Biol. Sci. 2023, 19 (9), 2648-2662. DOI: 10.7150/ijbs.81683.

NLM
Tseng JC, Yang JX, Lee CY, Lo CF, Liu YL, Zhang MM, Huang LR, Liu KJ, Wang CC, Huang CYF, Hong YR, Tsou LK, Chuang TH. Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug. Int J Biol Sci 2023; 19(9):2648-2662. doi:10.7150/ijbs.81683. https://www.ijbs.com/v19p2648.htm

CSE
Tseng JC, Yang JX, Lee CY, Lo CF, Liu YL, Zhang MM, Huang LR, Liu KJ, Wang CC, Huang CYF, Hong YR, Tsou LK, Chuang TH. 2023. Induction of Immune Responses and Phosphatidylserine Exposure by TLR9 Activation Results in a Cooperative Antitumor Effect with a Phosphatidylserine-targeting Prodrug. Int J Biol Sci. 19(9):2648-2662.

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