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The upregulation of immune checkpoints after photodynamic therapy reducing immune effect for treating breast cancer

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Abstract

The immune effect induced by photodynamic therapy (PDT) has a limited effect on breast tumor. This study hypothesized that suppressive immune checkpoints on T cells might upregulate after PDT, which may reduce the antitumor effect of PDT for treating breast tumor. This study explored the alteration of immune checkpoint for the first time. A bilateral subcutaneous transplanted breast tumor mice model was established, and right tumors imitated primary tumors, and left tumors imitated distant tumors. Primary tumors were treated with PDT mediated by hematoporphyrin derivatives (HpD-PDT). Costimulatory molecules (ICOS, OX40, and 4-1BB) and immune checkpoints (PD1, LAG-3, CTLA-4, TIM-3, TIGIT) on tumor infiltrating T cells after HpD-PDT were analyzed by flow cytometry. Antitumor and immune effects were also assessed after HpD-PDT combined with anti-PD1 and LAG-3 antibodies. Primary tumors were suppressed, but distant tumors could not be inhibited after HpD-PDT. The number of T cells was increased, but function did not enhance after HpD-PDT. Additionally, costimulatory molecules (ICOS, OX40, and 4-1BB) were not elevated, but the suppressive immune checkpoints on tumor infiltrating T cells were upregulated after HpD-PDT. Notably, PD1+ LAG-3+ CD4+ T and PD1+ LAG-3+ CD8+ T cells were significantly increased. When PD1 and LAG-3 blockade combined with HpD-PDT, both primary and distant tumors were significantly suppressed, and antitumor immune effects were significantly enhanced. HpD-PDT could upregulate the PD1+ LAG-3+ CD4+ T and PD1+ LAG-3+ CD8+ T cells. Dual blockade of PD1 and LAG-3 immune checkpoints can enhance the antitumor effect of HpD-PDT.

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Funding

This work was supported by the National Natural Science Foundation of China (61975239), the Beijing Natural Science Foundation (7222174), the Beijing Science and Technology New Star Program (Z211100002121168), and the Medical and Health Technology Innovation Project of the Chinese Academy of Medical Sciences (2019-I2M-5–061).

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Author notes

  1. Shan Long, Bo Wang, and Yingshu Cui contributed equally to this work.

  2. Xiaosong Li and Ying Gu contributed equally to this work.

Authors and Affiliations

  1. School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, 550025, China

    Shan Long, Bo Wang & Xiaosong Li

  2. School of Medicine, Nankai University, Tianjin, 300072, China

    Shan Long & Ying Gu

  3. Department of Laser Medicine, The First Medical Center of Chinese, PLA General Hospital, Haidian District, 28 Fuxing Road, Beijing, 100853, China

    Shan Long, Jiakang Shao, Yuanyuan Xu, Hui Li, Haixia Qiu, Jing Zeng & Ying Gu

  4. Medical School of Chinese PLA, Beijing, 100853, China

    Yingshu Cui, Jiakang Shao & Hui Li

  5. Department of Oncology, The Seventh Medical Center of Chinese, Dongcheng District, PLA General Hospital, 5 Nanmencang Hutong, DongshitiaoBeijing, 100039, China

    Yibing Zhao & Xiaosong Li

  6. College of Medical Technology, Beijing Institute of Technology, Beijing, 100081, China

    Hongyou Zhao & Defu Chen

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  1. Shan Long
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Contributions

Conceptualization: Shan Long, Xiaosong Li, and Ying Gu; data curation: Haixia Qiu, Hongyou Zhao, Jing Zeng, and Defu Chen; investigation: Shan Long, Yibing Zhao, Yuanyuan Xu, Bo Wang, and Hui Li; writing—original draft: Shan Long and Jiakang Shao; writing—review and editing: Xiaosong Li and Ying Gu; revising—manuscript: Bo Wang and Yingshu Cui.

Corresponding authors

Correspondence to Xiaosong Li or Ying Gu.

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Ethical approval

Animal experiment was performed according to the procedures previously approved by the Animal Ethics Committee of Chinese People’s Liberation Army General Hospital (approval 2019-X15-68).

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The authors declare no competing interests.

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Long, S., Wang, B., Cui, Y. et al. The upregulation of immune checkpoints after photodynamic therapy reducing immune effect for treating breast cancer. Lasers Med Sci 38, 243 (2023). https://doi.org/10.1007/s10103-023-03894-z

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