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      Improving antitumor immunity using antiangiogenic agents: Mechanistic insights, current progress, and clinical challenges


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          Cancer immunotherapy, especially immune checkpoint blockade (ICB), has revolutionized oncology. However, only a limited number of patients benefit from immunotherapy, and some cancers that initially respond to immunotherapy can ultimately relapse and progress. Thus, some studies have investigated combining immunotherapy with other therapies to overcome resistance to monotherapy. Recently, multiple preclinical and clinical studies have shown that tumor vasculature is a determinant of whether immunotherapy will elicit an antitumor response; thus, vascular targeting may be a promising strategy to improve cancer immunotherapy outcomes. A successful antitumor immune response requires an intact “Cancer‐Immunity Cycle,” including T cell priming and activation, immune cell recruitment, and recognition and killing of cancer cells. Angiogenic inducers, especially vascular endothelial growth factor (VEGF), can interfere with activation, infiltration, and function of T cells, thus breaking the “Cancer‐Immunity Cycle.” Together with immunostimulation‐regulated tumor vessel remodeling, VEGF‐mediated immunosuppression provides a solid therapeutic rationale for combining immunotherapy with antiangiogenic agents to treat solid tumors. Following the successes of recent landmark phase III clinical trials, therapies combining immune checkpoint inhibitors (ICIs) with antiangiogenic agents have become first‐line treatments for multiple solid tumors, whereas the efficacy of such combinations in other solid tumors remains to be validated in ongoing studies. In this review, we discussed synergies between antiangiogenic agents and cancer immunotherapy based on results from preclinical and translational studies. Then, we discussed recent progress in randomized clinical trials. ICI‐containing combinations were the focus of this review because of their recent successes, but combinations containing other immunotherapies were also discussed. Finally, we attempted to define critical challenges in combining ICIs with antiangiogenic agents to promote coordination and stimulate collaboration within the research community.


          In this review, mechanisms of VEGF‐induced immunosuppression based on results from preclinical and translational studies and recent progress in randomized clinical trials were discussed. Key challenges associated with dual targeting of VEGF and PD‐1/PD‐L1 pathways were also defined in order to stimulate collaboration and help galvanize a broader effort.

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Cancer Commun (Lond)
                Cancer Commun (Lond)
                Cancer Communications
                John Wiley and Sons Inc. (Hoboken )
                17 June 2021
                September 2021
                : 41
                : 9 ( doiID: 10.1002/cac2.v41.9 )
                : 830-850
                [ 1 ] The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology Wuhan University Wuhan Hubei 430079 P. R. China
                [ 2 ] Department of Oral Maxillofacial‐Head Neck Oncology School and Hospital of Stomatology Wuhan University Wuhan Hubei 430079 P. R. China
                Author notes
                [*] [* ] Correspondence

                Zhi‐Jun Sun, The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST), Key Laboratory of Oral Biomedicine Ministry of Education, Department of Oral Maxillofacial‐Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan 430079, Hubei, P. R. China.

                Email: sunzj@ 123456whu.edu.cn


                These authors contributed equally to this work.

                Author information
                © 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                : 07 May 2021
                : 08 March 2021
                : 11 June 2021
                Page count
                Figures: 5, Tables: 4, Pages: 21, Words: 12141
                Funded by: National Key Research and Development Program , doi 10.13039/501100012166;
                Award ID: 2017YFSF090107
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 82072996
                Award ID: 81874131
                Funded by: Hubei Province Natural Science Funds for Distinguished Young Scholar
                Award ID: 2017CFA062
                Funded by: Innovative research team of high‐level local universities in Shanghai
                Award ID: ZLCX20180500
                Custom metadata
                September 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:15.09.2021

                antiangiogenesis,bevacizumab,cancer,combination therapy,immune‐checkpoint inhibitor,immunotherapy,vascular endothelial growth factor


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