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Immune effects of α and β radionuclides in metastatic prostate cancer

Nature Reviews Urology (2024)Cite this article

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Abstract

External beam radiotherapy is used for radical treatment of organ-confined prostate cancer and to treat lesions in metastatic disease whereas molecular radiotherapy with labelled prostate-specific membrane antigen ligands and radium-223 (223Ra) is indicated for metastatic prostate cancer and has demonstrated substantial improvements in symptom control and overall survival compared with standard-of-care treatment. Prostate cancer is considered an immunologically cold tumour, so limited studies investigating the treatment-induced effects on the immune response have been completed. However, emerging data support the idea that radiotherapy induces an immune response in prostate cancer, but whether the response is an antitumour or pro-tumour response is dependent on the radiotherapy regime and is also cell-line dependent. In vitro data demonstrate that single-dose radiotherapy regimes induce a greater immune-suppressive profile than fractionated regimes; less is known about the immune response induced by molecular radiotherapy agents, but evidence suggests that these agents might induce an immune-suppressive systemic immune response, indicated by increased expression of inhibitory checkpoint molecules such as programmed cell death 1 ligand 1 and 2, and that these changes could be associated with clinical response. Different radiotherapy modalities can induce distinct immune profiles, which can either activate or suppress immune-mediated tumour killing and the current preclinical models used for prostate cancer research are not yet optimal for studying the complexity of the radiotherapy-induced immune response.

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Fig. 1: Radionuclides approved by the FDA or currently under investigation for prostate cancer.
Fig. 2: Immune cell composition of prostate cancer.
Fig. 3: Opposing immune activation and the immune-suppressive effects of radiotherapy.

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Acknowledgements

S.L. was supported by the Cancer Research UK Manchester Centre award (CTRQQR-2021\100010). P.H. and A.C. were supported by the NIHR Manchester Biomedical Research Centre (BRC-1215-20007). This work was funded by Peel Holdings and The Movember Foundation through the Manchester/Belfast Movember Centre of Excellence (CE013_2_004).

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  1. Division of Cancer Sciences, Oglesby Cancer Research Building, University of Manchester, Manchester, UK

    Sapna Lunj & Ananya Choudhury

  2. Nuclear Futures Institute, School of Computer Science and Engineering, Bangor University, Bangor, UK

    Tim Andrew Davies Smith

  3. Division of Cancer Sciences, Paterson Building, University of Manchester, Manchester, UK

    Kimberley Jayne Reeves, Jamie Honeychurch & Peter Hoskin

  4. The Dalton Cumbria Facility and the Department of Chemistry, University of Manchester, Manchester, UK

    Fred Currell

  5. Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK

    Jamie Honeychurch

  6. The Christie NHS Foundation Trust, Manchester, UK

    Ananya Choudhury

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S.L. researched data for the article. S.L., T.A.D.S., F.C., J.H., P.H. and A.C. contributed substantially to discussion of the content. S.L., F.C. and J.H. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Lunj, S., Smith, T.A.D., Reeves, K.J. et al. Immune effects of α and β radionuclides in metastatic prostate cancer. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00924-5

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