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Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

Abstract

Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.

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Figure 1: Direct effects of angiogenic factors on various immune cells.
Figure 2: The abnormal tumour vasculature contributes to immunosuppression in the tumour microenvironment.
Figure 3: Tumours secrete factors that cause systemic immunosuppression.
Figure 4: Vascular-normalizing therapies can reprogramme the immunosuppressive tumour microenvironment to an immunosupportive one.

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Acknowledgements

The work of the authors is supported in part by US National Institutes of Health (NIH) National Cancer Institute grants P01CA080124 (D.F, D.G.D., and R.K.J.), R01-CA096915 (D.F.), R01-CA159258 and R41-CA213678 (D.G.D.), and R01-CA129371, R01-CA208205, U01-CA 224348, and Outstanding Investigator Award R35-CA197743 and P50-CA165962 (R.K.J.). J.K. has received fellowships from the German Research Foundation (DFG) and the Solidar-Immun Foundation. Z.A. has received a fellowship from the Aid for Cancer Research Foundation and Tosteson Fund for Medical Discovery (FMD). R.K.J. has also received research funding from the Gates Foundation, the Ludwig Center at Harvard, the Lustgarten Foundation, and the National Foundation for Cancer Research. The authors thank M. Badeaux, M. Datta, Y. Huang, K. Jung, J. Martin, N. Wang, and C. Wong (who are all past or current fellows of the Edwin L. Steele Laboratories) for their critical reading of, and input into, this manuscript.

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J.K. and Z.A. contributed equally to the preparation of the manuscript. All authors made substantial contributions to researching data for the article, discussions of content, and the writing, reviewing, and editing of the manuscript.

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Correspondence to Rakesh K. Jain.

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Competing interests

D.G.D. has received consultancy fees from Bayer and research funding from Bayer, Bristol-Myers Squibb, Exelixis, Leap, and Merrimack. R.K.J. has received consultancy fees from Merck, Ophthotech, Pfizer, SPARC, and SynDevRx; owns equity in Enlight, Ophthotech, SynDevRx, and XTuit; and serves on the board of directors of XTuit and the boards of trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. D.F., Z.A., and J.K. do not have any conflicts of interest to declare.

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Fukumura, D., Kloepper, J., Amoozgar, Z. et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 15, 325–340 (2018). https://doi.org/10.1038/nrclinonc.2018.29

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