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Translational Therapeutics

Immunogenic hypofractionated radiotherapy sensitising head and neck squamous cell carcinoma to anti-PD-L1 therapy in MDSC-dependent manner

British Journal of Cancer volume 128, pages 2126–2139 (2023)Cite this article

Subjects

Abstract

Background

Enhancing the response rate of immunotherapy will aid in the success of cancer treatment. Here, we aimed to explore the combined effect of immunogenic radiotherapy with anti-PD-L1 treatment in immunotherapy-resistant HNSCC mouse models.

Methods

The SCC7 and 4MOSC2 cell lines were irradiated in vitro. SCC7-bearing mice were treated with hypofractionated or single-dose radiotherapy followed by anti-PD-L1 therapy. The myeloid-derived suppressive cells (MDSCs) were depleted using an anti-Gr-1 antibody. Human samples were collected to evaluate the immune cell populations and ICD markers.

Results

Irradiation increased the release of immunogenic cell death (ICD) markers (calreticulin, HMGB1 and ATP) in SCC7 and 4MOSC2 in a dose-dependent manner. The supernatant from irradiated cells upregulated the expression of PD-L1 in MDSCs. Mice treated with hypofractionated but not single-dose radiotherapy were resistant to tumour rechallenge by triggering ICD, when combined with anti-PD-L1 treatment. The therapeutic efficacy of combination treatment partially relies on MDSCs. The high expression of ICD markers was associated with activation of adaptive immune responses and a positive prognosis in HNSCC patients.

Conclusion

These results present a translatable method to substantially improve the antitumor immune response by combining PD-L1 blockade with immunogenic hypofractionated radiotherapy in HNSCC.

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Fig. 1: Irradiation-induced immunogenic cell death (ICD) in SCC7 and 4MOSC2 tumour cells in a dose-dependent manner.
Fig. 2: Irradiation upregulated PD-L1 expression on tumour cells and MDSCs.
Fig. 3: Radiotherapy (RT) enhanced the efficacy of anti-PD-L1 treatment in the mouse model.
Fig. 4: Fractionated radiotherapy (RT) induced immunogenic cell death (ICD) and promoted anti-PD-L1 treatment in a therapeutic study.
Fig. 5: The therapeutic efficacy of fractionated radiotherapy in combination with anti-PD-L1 or cisplatin.
Fig. 6: The therapeutic efficacy of anti-PD-L1 in combination with fractionated radiotherapy (RT) is dependent on the Gr-1+ myeloid cells.
Fig. 7: Phenotypic analysis of the tumour-infiltrating immune cells according to the expression of immunogenic cell death (ICD) markers among the prospective cohort of HNSCC patients.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We want to thank Shuyan Liang and Zhixin Qiu from Wuhan Biobank Co. Ltd., Hubei, China for their excellent technical assistance on flow cytometry and cells isolation. And we also want to thank Ji Chen, Yan-Peng Ding and Yan Qi from Zhongnan Hospital of Wuhan University and Ying Liu and Jin Jing from the Core Facility of Medical Research Institute at Wuhan University for their kind guidance on radiotherapy experiments.

Funding

This work was supported by the National Natural Science Foundation of China (NFSC): 82103333, 82072996, 81874131 and the Fundamental Research Funds for the Central Universities (2042021kf0174, 2042021kf0216).

Author information

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China

    Liang Mao, Jun-Jie Zhou, Yao Xiao, Qi-Chao Yang, Shao-Chen Yang, Shuo Wang, Zhi-Zhong Wu, Hong-Gang Xiong & Zhi-Jun Sun

  2. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 430079, Wuhan, China

    Liang Mao & Zhi-Jun Sun

  3. Department of Radiation and Medical Oncology, Hubei Province Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China

    Hai-Jun Yu

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  1. Liang Mao
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Contributions

The authors contributed in the following way: designed and performed the research: LM; wrote the manuscripts: LM, HY and ZS; data analysis: LM, JZ, YX, QY, SY, SW, ZW and HX; performed experiments: LM, JZ, YX, QY, SY, SW, ZW and HX; supervised the research: HY and ZS.

Corresponding authors

Correspondence to Hai-Jun Yu or Zhi-Jun Sun.

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The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments in this study were approved by the Institutional Animal Care and Use Committee (IACUC) of Wuhan University (2019038, 2019108, 2019161, 20220283). All experiments performed using the patients’ samples were reviewed and approved by the Institutional Medical Ethics Committee of School and Hospital of Stomatology, Wuhan University (2012LUNSHENZI46, 2018LUNSHENZIA28), and informed consent was obtained from all patients. All studies were conducted in accordance with the Declaration of Helsinki.

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Mao, L., Zhou, JJ., Xiao, Y. et al. Immunogenic hypofractionated radiotherapy sensitising head and neck squamous cell carcinoma to anti-PD-L1 therapy in MDSC-dependent manner. Br J Cancer 128, 2126–2139 (2023). https://doi.org/10.1038/s41416-023-02230-0

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