Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Data availability

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

References

  1. Galon J, Bruni D. Tumor immunology and tumor evolution: intertwined histories. Immunity. 2020;52:55–81.

    Article  CAS  PubMed  Google Scholar 

  2. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018–28.

    Article  PubMed  Google Scholar 

  4. Burtness B, Harrington KJ, Greil R, Soulieres D, Tahara M, de Castro G Jr. et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915–28.

    Article  CAS  PubMed  Google Scholar 

  5. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Whiteside TL. Head and neck carcinoma immunotherapy: facts and hopes. Clin Cancer Res. 2018;24:6–13.

    Article  CAS  PubMed  Google Scholar 

  7. Mandal R, Senbabaoglu Y, Desrichard A, Havel JJ, Dalin MG, Riaz N, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight. 2016;1:e89829.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab vs investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018;81:45–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375:1856–67.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34:3838–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cohen EEW, Soulieres D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019;393:156–67.

    Article  CAS  PubMed  Google Scholar 

  12. Powell SF, Gold KA, Gitau MM, Sumey CJ, Lohr MM, McGraw SC, et al. Safety and efficacy of pembrolizumab with chemoradiotherapy in locally advanced head and neck squamous cell carcinoma: a phase IB study. J Clin Oncol. 2020;38:2427–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Weiss J, Sheth S, Deal AM, Grilley Olson JE, Patel S, Hackman TG, et al. Concurrent definitive immunoradiotherapy for patients with stage III-IV head and neck cancer and cisplatin contraindication. Clin Cancer Res. 2020;26:4260–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021;22:450–62.

    Article  CAS  PubMed  Google Scholar 

  15. Demaria S, Coleman CN, Formenti SC. Radiotherapy: changing the game in immunotherapy. Trends Cancer. 2016;2:286–94.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Karam SD, Raben D. Radioimmunotherapy for the treatment of head and neck cancer. Lancet Oncol. 2019;20:e404–16.

    Article  CAS  PubMed  Google Scholar 

  17. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97–111.

    Article  CAS  PubMed  Google Scholar 

  18. Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014;41:843–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Oweida AJ, Darragh L, Phan A, Binder D, Bhatia S, Mueller A, et al. STAT3 modulation of regulatory T cells in response to radiation therapy in head and neck cancer. J Natl Cancer Inst. 2019;111:1339–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jayaraman P, Parikh F, Newton JM, Hanoteau A, Rivas C, Krupar R, et al. TGF-beta1 programmed myeloid-derived suppressor cells (MDSC) acquire immune-stimulating and tumor killing activity capable of rejecting established tumors in combination with radiotherapy. Oncoimmunology. 2018;7:e1490853.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Lin L, Kane N, Kobayashi N, Kono EA, Yamashiro JM, Nickols NG, et al. High-dose per fraction radiotherapy induces both antitumor immunity and immunosuppressive responses in prostate tumors. Clin Cancer Res. 2021;27:1505–15.

    Article  CAS  PubMed  Google Scholar 

  22. Oweida A, Hararah MK, Phan A, Binder D, Bhatia S, Lennon S, et al. Resistance to radiotherapy and PD-L1 blockade is mediated by TIM-3 upregulation and regulatory T-cell infiltration. Clin Cancer Res. 2018;24:5368–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124:687–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vanpouille-Box C, Diamond JM, Pilones KA, Zavadil J, Babb JS, Formenti SC, et al. TGFbeta is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 2015;75:2232–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74:5458–68.

    Article  CAS  PubMed  Google Scholar 

  26. Oweida A, Lennon S, Calame D, Korpela S, Bhatia S, Sharma J, et al. Ionizing radiation sensitizes tumors to PD-L1 immune checkpoint blockade in orthotopic murine head and neck squamous cell carcinoma. Oncoimmunology. 2017;6:e1356153.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Newton JM, Hanoteau A, Liu HC, Gaspero A, Parikh F, Gartrell-Corrado RD, et al. Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition. J Immunother Cancer. 2019;7:216.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wennerberg E, Spada S, Rudqvist NP, Lhuillier C, Gruber S, Chen Q, et al. CD73 blockade promotes dendritic cell infiltration of irradiated tumors and tumor rejection. Cancer Immunol Res. 2020;8:465–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang Z, Wu VH, Allevato MM, Gilardi M, He Y, Luis Callejas-Valera J, et al. Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4. Nat Commun. 2019;10:5546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO classification of head and neck tumours. Lyon, Fracnce: International Agency for Research on Cancer (IARC); 2017.

  31. Huang CF, Chen L, Li YC, Wu L, Yu GT, Zhang WF, et al. NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma. J Exp Clin Cancer Res. 2017;36:116.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Wu L, Mao L, Liu JF, Chen L, Yu GT, Yang LL, et al. Blockade of TIGIT/CD155 signaling reverses T-cell exhaustion and enhances antitumor capability in head and neck squamous cell carcinoma. Cancer Immunol Res. 2019;7:1700–13.

    Article  CAS  PubMed  Google Scholar 

  33. Roberts EW, Broz ML, Binnewies M, Headley MB, Nelson AE, Wolf DM, et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming of T cell immunity in melanoma. Cancer Cell. 2016;30:324–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Golden EB, Frances D, Pellicciotta I, Demaria S, Helen Barcellos-Hoff M, Formenti SC. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology. 2014;3:e28518.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M. Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. Oral Oncol. 2016;57:54–60.

    Article  CAS  PubMed  Google Scholar 

  36. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19:108–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Xu J, Escamilla J, Mok S, David J, Priceman S, West B, et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 2013;73:2782–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10:417–27.

    Article  CAS  PubMed  Google Scholar 

  39. Sharabi AB, Lim M, DeWeese TL, Drake CG. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncol. 2015;16:e498–509.

    Article  PubMed  Google Scholar 

  40. Pfister DG, Spencer S, Adelstein D, Adkins D, Anzai Y, Brizel DM, et al. Head and neck cancers, version 2.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2020;18:873–98.

    Article  Google Scholar 

  41. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48:812–30.e814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dudzinski SO, Cameron BD, Wang J, Rathmell JC, Giorgio TD, Kirschner AN. Combination immunotherapy and radiotherapy causes an abscopal treatment response in a mouse model of castration resistant prostate cancer. J Immunother Cancer. 2019;7:218.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Poty S, Carter LM, Mandleywala K, Membreno R, Abdel-Atti D, Ragupathi A, et al. Leveraging bioorthogonal click chemistry to improve (225)Ac-radioimmunotherapy of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2019;25:868–80.

    Article  CAS  PubMed  Google Scholar 

  44. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009;15:5379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Galluzzi L, Kepp O, Kroemer G. Immunogenic cell death in radiation therapy. Oncoimmunology. 2013;2:e26536.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial liaison? Nat Rev Clin Oncol. 2017;14:365–79.

    Article  CAS  PubMed  Google Scholar 

  47. Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, van Endert P, et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 2007;14:1848–50.

    Article  CAS  PubMed  Google Scholar 

  48. Werthmoller N, Frey B, Wunderlich R, Fietkau R, Gaipl US. Modulation of radiochemoimmunotherapy-induced B16 melanoma cell death by the pan-caspase inhibitor zVAD-fmk induces anti-tumor immunity in a HMGB1-, nucleotide- and T-cell-dependent manner. Cell Death Dis. 2015;6:e1761.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ko A, Kanehisa A, Martins I, Senovilla L, Chargari C, Dugue D, et al. Autophagy inhibition radiosensitizes in vitro, yet reduces radioresponses in vivo due to deficient immunogenic signalling. Cell Death Differ. 2014;21:92–9.

    Article  CAS  PubMed  Google Scholar 

  50. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4:127ra137.

    Article  Google Scholar 

  51. Campian JL, Sarai G, Ye X, Marur S, Grossman SA. Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. Head Neck. 2014;36:1747–53.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bernstein MB, Krishnan S, Hodge JW, Chang JY. Immunotherapy and stereotactic ablative radiotherapy (ISABR): a curative approach? Nat Rev Clin Oncol. 2016;13:516–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, et al. Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol Res. 2020;8:1440–51.

    Article  CAS  PubMed  Google Scholar 

  54. Oweida AJ, Mueller AC, Piper M, Milner D, Van Court B, Bhatia S, et al. Response to radiotherapy in pancreatic ductal adenocarcinoma is enhanced by inhibition of myeloid-derived suppressor cells using STAT3 anti-sense oligonucleotide. Cancer Immunol Immunother. 2021;70:989–1000.

    Article  CAS  PubMed  Google Scholar 

  55. Morisada M, Clavijo PE, Moore E, Sun L, Chamberlin M, Van Waes C, et al. PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation. Oncoimmunology. 2018;7:e1395996.

    Article  PubMed  Google Scholar 

  56. Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015;15:409–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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

Authors
  1. Liang Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jun-Jie Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yao Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi-Chao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shao-Chen Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shuo Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhi-Zhong Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hong-Gang Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hai-Jun Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhi-Jun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

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.

Consent for publication

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02230-0

This article is cited by

Search

Advanced search

Quick links