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TGF-β1 mediates tumor immunosuppression aggravating at the late stage post-high-light-dose photodynamic therapy

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Abstract

Photodynamic therapy (PDT) is an emerging clinical treatment that is expected to become an important adjuvant strategy for the immunotherapeutic cancer treatment. Recently, numerous works have reported combination strategies. However, clinical data showed that the anti-tumor immune response of PDT was not lasting though existing. The immune activation effect will eventually turn to immunosuppressive effect and get aggravated at the late stage post-PDT. So far, the mechanism is still unclear, which limits the design of specific correction strategies and further development of PDT. Several lines of evidence suggest a role for TGF-β1 in the immunosuppression associated with PDT. Herein, this study systematically illustrated the dynamic changes of immune states post-PDT within the tumor microenvironment. The results clearly demonstrated that high-light-dose PDT, as a therapeutic dose, induced early immune activation followed by late immunosuppression, which was mediated by the activated TGF-β1 upregulation. Then, the mechanism of PDT-induced TGF-β1 accumulation and immunosuppression was elucidated, including the ROS/TGF-β1/MMP-9 positive feedback loop and CD44-mediated local amplification, which was further confirmed by spatial transcriptomics, as well as by the extensive immune inhibitory effect of local high concentration of TGF-β1. Finally, a TGF-β blockade treatment strategy was presented as a promising combinational strategy to reverse high-light-dose PDT-associated immunosuppression. The results of this study provide new insights for the biology mechanism and smart improvement approaches to enhance tumor photodynamic immunotherapy.

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Data availability

All the data supporting the findings of this study are available within the article and its Supplementary Information files and from the corresponding authors upon reasonable request.

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Funding

This study was supported by the National Natural Science Foundation of China (82173954, 81801819, 82204340), China Postdoctoral Science Foundation (2021T140504, 2020M682230, 2022M723508), Natural Science Foundation of Shandong Province of China (ZR2020MH295), Natural Science Foundation of Jiangsu Province of China (BK20221048), Jiangsu Funding Program for Excellent Postdoctoral Talent (2022ZB295) and State Drug Administration-Key Laboratory of Quality Control of Chinese Medicinal Materials and Detection Pieces (2022GSMPA-KL06).

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Author notes

  1. Lingfei Han and Xiaoxian Huang have contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, China

    Lingfei Han, Hongtan Zhu, Ruyi Wang, Honglei Lin & Wenyuan Liu

  2. Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 211198, China

    Xiaoxian Huang, Bin Zhao & Feng Feng

  3. Tumor Precise Intervention and Translational Medicine Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, China

    Bin Zhao, Shaoxia Liu, Fulei Liu & Jingwei Xue

  4. Pharmaceutical Department, The Affiliated Taian City Central Hospital of Qingdao University, Taian, 271000, China

    Fulei Liu

  5. Zhejiang Center for Safety Study of Drug Substances (Industrial Technology Innovation Platform), Hangzhou, 310018, China

    Wenyuan Liu

  6. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China

    Feng Feng

  7. Gansu Institute for Drug Control, Gansu, 730000, China

    Xiao Ma

Authors
  1. Lingfei Han
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Contributions

LH did conceptualization, methodology, investigation, validation, writing—original draft. XH performed methodology, investigation, validation, and formal analysis. BZ done methodology and investigation. HZ was involved in formal analysis and visualization. RW done visualization. SL and HL contributed to methodology. FF supervised the study. XM did funding acquisition. FL was involved in conceptualization and funding acquisition. JX did funding acquisition and supervision. WL performed funding acquisition, supervision, and project administration.

Corresponding authors

Correspondence to Fulei Liu, Jingwei Xue or Wenyuan Liu.

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All animal experiments were performed according to the guidelines for laboratory animals established by China Pharmaceutical University (SYXK 2021-0011).

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Han, L., Huang, X., Zhao, B. et al. TGF-β1 mediates tumor immunosuppression aggravating at the late stage post-high-light-dose photodynamic therapy. Cancer Immunol Immunother 72, 3079–3095 (2023). https://doi.org/10.1007/s00262-023-03479-3

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