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Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa

Nature Reviews Clinical Oncology volume 15, pages 310–324 (2018)Cite this article

Subjects

Key Points

  • Proteins with major roles in angiogenesis can also have direct or indirect effects on components of the immune system, most often resulting in immunosuppressive outcomes

  • The tumour vasculature can upregulate or downregulate proteins that control the homing and trafficking of immune cells, creating a selective immune-cell barrier on endothelium

  • The use of anti-angiogenic drugs and other vascular-targeting agents can normalize and remodel the tortuous tumour vasculature, enabling alleviation of hypoxia and efficient tumour infiltration by effector immune cells

  • Combinations of anti-angiogenic agents with various immunotherapies, including immune-checkpoint inhibitors, have been shown preclinically to generate more-potent antitumour effects and might have clinical potential

  • Anti-angiogenic agents can alleviate immunosuppression, and conversely, immunotherapies can induce changes in the vasculature or bring about antivascular effects; thus, immunotherapy and/or anti-angiogenic therapies have the potential to create a cycle of immunostimulation and vascular remodelling within tumours

Abstract

Immunotherapies have revolutionized medical oncology following the remarkable and, in some cases, unprecedented outcomes observed in certain groups of patients with cancer. Combination with other therapeutic modalities, including anti-angiogenic agents, is one of the many strategies currently under investigation to improve the response rates and duration of immunotherapies. Such a strategy might seem counterintuitive given that anti-angiogenic agents can increase tumour hypoxia and reduce the number of blood vessels within tumours. Herein, we review the additional effects mediated by drugs targeting VEGF-dependent signalling and other pathways, such as those mediated by angiopoietin 2 or HGF, which might increase the efficacy of immunotherapies. In addition, we discuss the seldom considered possibility that immunotherapies, and immune-checkpoint inhibitors in particular, might increase the efficacy of anti-angiogenic or other types of antivascular therapies and/or promote changes in the tumour vasculature. In short, we propose that interactions between both therapeutic modalities could be considered a 'two-way street'.

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Figure 1: Angiogenesis-modulating factors have effects on the immune system in three established ways.
Figure 2: A proposed immunostimulatory vascular-modulating cycle.

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Acknowledgements

R.S.K.'s research on anti-angiogenic drugs and/or immunotherapies has been supported over the past 2 years by grants from the Canadian Breast Cancer Foundation (CBCF), the Canadian Institutes of Health Research (CIHR), and Worldwide Cancer Research (WCR).

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  1. Department of Medical Biophysics, Biological Sciences Platform, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada

    Kabir A. Khan & Robert S. Kerbel

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K.A.K. and R.S.K. both contributed to researching data for the article, discussions of content, writing the manuscript, and editing and reviewing the manuscript before publication.

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Correspondence to Kabir A. Khan or Robert S. Kerbel.

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Competing interests

R.S.K. has sponsored research agreements with Boehringer Ingelheim, Neovacs, and Genentech. R.S.K. has received honoraria recently from Boehringer Ingelheim, NED Biosystems, Merck Pharmaceuticals, Apobiologix, and Onkaido and consultant fees for Neovacs. K.A.K. declares no competing interests.

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Khan, K., Kerbel, R. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15, 310–324 (2018). https://doi.org/10.1038/nrclinonc.2018.9

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