Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

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Abstract

Angiogenesis is the process through which novel blood vessels are formed from pre-existing ones and it is involved in both physiological and pathological processes of the body. Furthermore, tumor angiogenesis is a crucial factor associated with tumor growth, progression, and metastasis. In this manner, there has been a great interest in the development of anti-angiogenesis strategies that could inhibit tumor vascularization. Conventional approaches comprise the administration of anti-angiogenic drugs that target and block the activity of proangiogenic factors. However, as their efficacy is still a matter of debate, novel strategies have been focusing on combining anti-angiogenic agents with chemotherapy or immunotherapy. Moreover, nanotechnology has also been investigated for the potential of nanomaterials to target and release anti-angiogenic drugs at specific sites. The aim of this paper is to review the mechanisms involved in angiogenesis and tumor vascularization and provide an overview of the recent trends in anti-angiogenic strategies for cancer therapy.

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Mutual Regulation of Tumour Vessel Normalization and Immunostimulatory Reprogramming

Lin Tian, Amit Goldstein, Hai Wang … (2017)

Blockade of angiogenesis can retard tumour growth, but may also paradoxically increase metastasis 1,2 . Vessel normalization (VN) may resolve this paradox 3 . VN involves increased pericyte coverage, improved tumour vessel perfusion, reduced vascular permeability, and consequently mitigated hypoxia 3 . While these processes alter tumour progression, their regulation is poorly understood. Here we show that Type 1 T helper (Th1) cells play a crucial role in VN. Bioinformatic analyses revealed that gene expression features related to VN correlate with immunostimulatory pathways, especially T lymphocyte (TL) infiltration/activities. To delineate the causal relationship, we employed various mouse models with VN or TL deficiencies. While VN disruption reduced TL infiltration as expected 4 , reciprocal depletion or inactivation of CD4+-TLs decreased VN, indicating a mutually-regulatory loop. Additionally, CD4+-TL activation by immune checkpoint blockade (ICB) increased VN. IFNγ+ Th1 cells are the major population associated with VN. Patient-derived xenograft (PDX) tumours growing in immunodeficient animal hosts exhibited enhanced hypoxia compared to the original tumours in immunocompetent human hosts, which was reduced by adoptive Th1 transfer. Our findings elucidate an unexpected role of Th1 in vasculature and immune reprogramming. Th1 cells may be a marker and a determinant of both ICB and anti-angiogenesis efficacies.

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Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation

Elizabeth Allen, Arnaud Jabouille, Lee B. Rivera … (2017)

Inhibitors of VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) are commonly used in the clinic, but their beneficial effects are only observed in a subset of patients and limited by induction of diverse relapse mechanisms. We describe the up-regulation of an adaptive immunosuppressive pathway during antiangiogenic therapy, by which PD-L1 (programmed cell death ligand 1), the ligand of the negative immune checkpoint regulator PD-1 (programmed cell death protein 1), is enhanced by interferon-γ-expressing T cells in distinct intratumoral cell types in refractory pancreatic, breast, and brain tumor mouse models. Successful treatment with a combination of anti-VEGFR2 and anti-PD-L1 antibodies induced high endothelial venules (HEVs) in PyMT (polyoma middle T oncoprotein) breast cancer and RT2-PNET (Rip1-Tag2 pancreatic neuroendocrine tumors), but not in glioblastoma (GBM). These HEVs promoted lymphocyte infiltration and activity through activation of lymphotoxin β receptor (LTβR) signaling. Further activation of LTβR signaling in tumor vessels using an agonistic antibody enhanced HEV formation, immunity, and subsequent apoptosis and necrosis in pancreatic and mammary tumors. Finally, LTβR agonists induced HEVs in recalcitrant GBM, enhanced cytotoxic T cell (CTL) activity, and thereby sensitized tumors to antiangiogenic/anti-PD-L1 therapy. Together, our preclinical studies provide evidence that anti-PD-L1 therapy can sensitize tumors to antiangiogenic therapy and prolong its efficacy, and conversely, antiangiogenic therapy can improve anti-PD-L1 treatment specifically when it generates intratumoral HEVs that facilitate enhanced CTL infiltration, activity, and tumor cell destruction.

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Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment

Ming Yi, Dechao Jiao, Shuang Qin … (2019)

Immune checkpoint inhibitor (ICI) activates host’s anti-tumor immune response by blocking negative regulatory immune signals. A series of clinical trials showed that ICI could effectively induce tumor regression in a subset of advanced cancer patients. In clinical practice, a main concerning for choosing ICI is the low response rate. Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. However, some recent studies indicated that ICI resistance could be alleviated by combination therapy with anti-angiogenesis treatment. Actually, anti-angiogenesis therapy not only prunes blood vessel which is essential to cancer growth and metastasis, but also reprograms the tumor immune microenvironment. Preclinical studies demonstrated that the efficacy of combination therapy of ICI and anti-angiogenesis was superior to monotherapy. In mice model, combination therapy could effectively increase the ratio of anti-tumor/pro-tumor immune cell and decrease the expression of multiple immune checkpoints more than PD-1. Based on exciting results from preclinical studies, many clinical trials were deployed to investigate the synergistic effect of the combination therapy and acquired promising outcome. This review summarized the latest understanding of ICI combined anti-angiogenesis therapy and highlighted the advances of relevant clinical trials.

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Journal

Journal ID (nlm-ta): J Clin Med

Journal ID (iso-abbrev): J Clin Med

Journal ID (publisher-id): jcm

Title: Journal of Clinical Medicine

Publisher: MDPI

ISSN (Electronic): 2077-0383

Publication date (Electronic): 29 December 2019

Publication date Collection: January 2020

Volume: 9

Issue: 1

Electronic Location Identifier: 84

Affiliations

[1 ]“Victor Gomoiu” Clinical Children’s Hospital, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; raluca.teleanu@ 123456umfcd.ro

[2 ]Faculty of Engineering in Foreign Languages, 060042 Bucharest, Romania; cristina.chircov@ 123456yahoo.com

[3 ]Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, Politehnica University of Bucharest, 011061 Bucharest, Romania

[4 ]Emergency University Hospital, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; daniel.teleanu@ 123456umfcd.ro

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[* ]Correspondence: grumezescu@ 123456yahoo.com ; Tel.: +40-21-402-39-97

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Cristina Chircov https://orcid.org/0000-0002-8695-6884

Alexandru Mihai Grumezescu https://orcid.org/0000-0003-3036-094X

Article

Publisher ID: jcm-09-00084

DOI: 10.3390/jcm9010084

PMC ID: 7020037

PubMed ID: 31905724

SO-VID: c9cd6f10-c12f-42c3-8de1-428a151c9463

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

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Cancer Immunotherapy

Most cited references 137

Mutual Regulation of Tumour Vessel Normalization and Immunostimulatory Reprogramming

Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation

Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment

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