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  • Perspective
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Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes

Nature Reviews Clinical Oncology volume 18, pages 527–540 (2021)Cite this article

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Abstract

Immune checkpoint inhibitors have revolutionized medical oncology, although currently only a subset of patients has a response to such treatment. A compelling body of evidence indicates that anti-angiogenic therapy has the capacity to ameliorate antitumour immunity owing to the inhibition of various immunosuppressive features of angiogenesis. Hence, combinations of anti-angiogenic agents and immunotherapy are currently being tested in >90 clinical trials and 5 such combinations have been approved by the FDA in the past few years. In this Perspective, we describe how the angiogenesis-induced endothelial immune cell barrier hampers antitumour immunity and the role of endothelial cell anergy as the vascular counterpart of immune checkpoints. We review the antitumour immunity-promoting effects of anti-angiogenic agents and provide an update on the current clinical successes achieved when these agents are combined with immune checkpoint inhibitors. Finally, we propose that anti-angiogenic agents are immunotherapies — and vice versa — and discuss future research priorities.

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Fig. 1: The endothelial immune cell barrier.
Fig. 2: Endothelial cell anergy.
Fig. 3: Molecular mechanisms of endothelial cell anergy.
Fig. 4: Endothelial cell anergy is a vascular immune checkpoint.

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Acknowledgements

The work of P.N-S. is funded by the Swiss National Science Foundation (grant 310030_197878). The work of A.W.G. is supported by the KWF Cancer Society (grant 2018–11651).

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Authors and Affiliations

  1. Angiogenesis Laboratory, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands

    Zowi R. Huinen, Elisabeth J. M. Huijbers, Judy R. van Beijnum & Arjan W. Griffioen

  2. Molecular Pharmacology Group, School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland

    Patrycja Nowak-Sliwinska

  3. Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland

    Patrycja Nowak-Sliwinska

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  1. Zowi R. Huinen
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  2. Elisabeth J. M. Huijbers
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  3. Judy R. van Beijnum
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Z.R.H. and A.W.G. researched data for this article. All authors contributed to all other aspects of preparation of this manuscript.

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Nature Reviews Clinical Oncology thanks M. de Palma, who co-reviewed with A. Martinez-Usatorre, R. Kerbel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Huinen, Z.R., Huijbers, E.J.M., van Beijnum, J.R. et al. Anti-angiogenic agents — overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol 18, 527–540 (2021). https://doi.org/10.1038/s41571-021-00496-y

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