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  • Review Article
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Roles of the RANKL–RANK axis in antitumour immunity — implications for therapy

Nature Reviews Clinical Oncology volume 15, pages 676–693 (2018)Cite this article

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Abstract

Recognizing that the transformative effects of immunotherapy are currently limited to a minority of patients with cancer, research efforts are increasingly focused on expanding and enhancing clinical responses by combining immunotherapies; the repurposing of existing drugs is an attractive approach, given their well-characterized safety and pharmacokinetic profiles. Receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were initially described in the context of T cell–dendritic cell interactions; however, the discovery of an obligate role of RANK signalling in osteoclastogenesis led to the development of the anti-RANKL antibody denosumab for antiresorptive indications, including bone metastases. Randomized clinical trials and post-marketing surveillance studies have established the acceptable safety profile of denosumab. More recently, several case reports involving patients with advanced-stage melanoma have described remarkable responses following concurrent treatment with denosumab and immune-checkpoint inhibitors. Randomized trials assessing similar combinations in patients with melanoma or renal cell carcinoma are now underway. Herein, we discuss the hallmark clinical trials of denosumab in light of possible immunological effects of this agent. We highlight the role of immune cells as sources of RANK and RANKL in the tumour microenvironment and review data on RANKL inhibition in mouse models of cancer. Finally, we describe hypothetical immune-related mechanisms of action, which could be assessed in clinical trials of immune-checkpoint inhibitors and denosumab in patients with cancer.

Key points

  • Receptor activator of nuclear factor-κB ligand (RANKL) and its cognate receptor, RANK, are expressed by distinct immune cells in the tumour microenvironment (TME) and might also be expressed in tumour cells, the stroma, and non-malignant tissues.

  • Accumulating observational and preclinical evidence suggests that RANKL–RANK interactions between cells in the TME have immunosuppressive effects.

  • Endogenous inhibitors of RANKL include soluble osteoprotegerin (OPG) and leucine-rich repeat-containing G protein-coupled receptor 4; pharmacological inhibitors include denosumab (a monoclonal antibody) and an OPG–Fc fusion protein (discontinued from clinical development after phase I trials).

  • Denosumab is FDA approved for indications including the prevention of skeletal-related events arising from bone metastases in cancer; however, several trials are now testing the immune anticancer activities of denosumab, including as a partner to immune-checkpoint inhibitors.

  • Among immune cells infiltrating human or mouse cancers, RANK can be expressed on immature dendritic cells, immunosuppressive M2-type macrophages, myeloid-derived suppressor cells, and natural killer cells, whereas CD8+ and CD4+ T cells (including regulatory T cells) can express RANKL.

  • Possible mechanisms whereby RANKL inhibition could improve the effects of immune-checkpoint inhibition in cancer include interruption of an immunosuppressive myeloid–lymphocyte axis, cross-modulation of the TME, and interruption of central tolerance.

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Fig. 1: RANKL–RANK interaction and its inhibitors.
Fig. 2: Expression of RANK and RANKL in the TME and locoregional lymph nodes.
Fig. 3: Inflammatory or tolerogenic consequences of RANK ligation on myeloid cells and DCs are context dependent.
Fig. 4: Proposed mechanisms by which RANKL inhibition can improve antitumour immunity.

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Acknowledgements

The work of E.A. has been supported by a University of Queensland Australian Postgraduate Award. The work of M.J.S. has been supported by a National Health and Medical Research Council (NHMRC) Senior Principal Research Fellowship (grant 1078671), an NHMRC Program Grant (grant 1132519), and The Cancer Council of Queensland (grant 1102242). The work of M.W.L.T. has been supported by a New Concept Grant funded by It’s a Bloke Thing through the Prostate Cancer Foundation of Australia’s Research Program.

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Nature Reviews Clinical Oncology thanks B. Boyle, F. Saad and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. These authors contributed equally: William C. Dougall, Michele W. L. Teng.

Authors and Affiliations

  1. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

    Elizabeth Ahern, Mark J. Smyth & William C. Dougall

  2. Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

    Elizabeth Ahern & Michele W. L. Teng

  3. School of Medicine, University of Queensland, Herston, Queensland, Australia

    Elizabeth Ahern, Mark J. Smyth & Michele W. L. Teng

  4. Medical Oncology, Royal Brisbane and Women’s Hospital, Herston, Queensland, Australia

    Elizabeth Ahern

  5. Immuno-Oncology Discovery Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

    William C. Dougall

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E.A. researched data for the article, E.A., W.C.D., and M.W.L.T made substantial contributions to discussions of content and writing the manuscript, and all authors reviewed and/or edited the manuscript before submission.

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M.J.S. has received research funding from Aduro Biotech, Bristol-Myers Squibb, and Tizona Therapeutics. W.C.D. has received speaker’s honoraria from Amgen. M.W.L.T. has received speaker’s honoraria from Arcus Biosciences, Boehringer Ingelheim, and MSD. E.A. declares no competing interests.

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Ahern, E., Smyth, M.J., Dougall, W.C. et al. Roles of the RANKL–RANK axis in antitumour immunity — implications for therapy. Nat Rev Clin Oncol 15, 676–693 (2018). https://doi.org/10.1038/s41571-018-0095-y

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