Persistent restoration to the immunosupportive tumor microenvironment in glioblastoma by bevacizumab

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Abstract

Although vascular endothelial growth factor ( VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 ( PD‐1)/PD ligand‐1 ( PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group ( P < .01 for each). The PD‐1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group ( P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group ( CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor‐associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post‐Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long‐term Bev therapy.

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Most cited references 27

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Ivraym B Barsoum, Chelsea A Smallwood, D Robert Siemens … (2014)

Immune escape is a fundamental trait of cancer in which mechanistic knowledge is incomplete. Here, we describe a novel mechanism by which hypoxia contributes to tumoral immune escape from cytotoxic T lymphocytes (CTL). Exposure of human or murine cancer cells to hypoxia for 24 hours led to upregulation of the immune inhibitory molecule programmed cell death ligand-1 (PD-L1; also known as B7-H1), in a manner dependent on the transcription factor hypoxia-inducible factor-1α (HIF-1α). In vivo studies also demonstrated cellular colocalization of HIF-1α and PD-L1 in tumors. Hypoxia-induced expression of PD-L1 in cancer cells increased their resistance to CTL-mediated lysis. Using glyceryl trinitrate (GTN), an agonist of nitric oxide (NO) signaling known to block HIF-1α accumulation in hypoxic cells, we prevented hypoxia-induced PD-L1 expression and diminished resistance to CTL-mediated lysis. Moreover, transdermal administration of GTN attenuated tumor growth in mice. We found that higher expression of PD-L1 induced in tumor cells by exposure to hypoxia led to increased apoptosis of cocultured CTLs and Jurkat leukemia T cells. This increase in apoptosis was prevented by blocking the interaction of PD-L1 with PD-1, the PD-L1 receptor on T cells, or by addition of GTN. Our findings point to a role for hypoxia/HIF-1 in driving immune escape from CTL, and they suggest a novel cancer immunotherapy to block PD-L1 expression in hypoxic-tumor cells by administering NO mimetics.

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Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3zeta subunit in the tumor-associated T cells. However, increased percentages of CD4(+)CD25(+) T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4(+)CD25(+) T cells were found to secrete transforming growth factor-beta, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8(+) T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-gamma, and tumor necrosis factor-alpha secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4(+)CD25(+) T cells that secrete the immunosuppressive cytokine transforming growth factor-beta. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8(+) T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.

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VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression.

Dmitry I. Gabrilovich, Kelly S Parman, Ekaterina Kisseleva … (2003)

T-cell defects and premature thymic atrophy occur in cancer patients and tumor-bearing animals. We demonstrate that exposure of mice to recombinant vascular endothelial growth factor (VEGF) at concentrations similar to those observed in advanced stage cancer patients reproduces this profound thymic atrophy and is highlighted by a dramatic reduction in CD4+/CD8+ thymocytes. We find that VEGF does not induce thymocyte apoptosis, but instead rapidly decreases the number of the earliest observable progenitors in the thymus. VEGF does not inhibit thymocyte development in fetal thymic organ culture, further suggesting a prethymic effect. We also demonstrate that bone marrow progenitors from animals infused with recombinant VEGF and transferred to irradiated untreated animals recolonize the thymus more efficiently than progenitors from control animals. This suggests that VEGF exposure is associated with an increased population of thymus-committed progenitors in the bone marrow. We hypothesize that pathophysiologically relevant concentrations of VEGF may block the differentiation and/or emigration of these progenitors resulting in the observed thymic atrophy. Removal of VEGF via cessation of infusion or adoptive transfer of progenitors to a congenic host induces a preferential commitment of lymphoid progenitors to the T lineage and results in a restoration of the normal composition and cellularity of the thymus. These data demonstrate that at pathophysiologic concentrations, VEGF interferes with the development of T cells from early hematopoetic progenitor cells and this may contribute to tumor-associated immune deficiencies.

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Author and article information

Contributors

Toshihide Tanaka: ttanaka@jikei.ac.jp

Hikaru Sasaki:

ORCID: https://orcid.org/0000-0001-7380-1931

hsasaki@keio.jp

Journal

Journal ID (nlm-ta): Cancer Sci

Journal ID (iso-abbrev): Cancer Sci

Journal ID (doi): 10.1111/(ISSN)1349-7006

Journal ID (publisher-id): CAS

Title: Cancer Science

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 1347-9032

ISSN (Electronic): 1349-7006

Publication date (Electronic): 21 December 2018

Publication date (Print): February 2019

Volume: 110

Issue: 2 ( doiID: 10.1111/cas.2019.110.issue-2 )

Pages: 499-508

Affiliations

[ ¹ ] Department of Neurosurgery Keio University School of Medicine Tokyo Japan

[ ² ] Department of Neurosurgery Jikei University Kashiwa Hospital Chiba Japan

[ ³ ] Division of Diagnostic Pathology Keio University School of Medicine Tokyo Japan

[ ⁴ ] Department of Neurosurgery Kagawa University Hospital Kagawa Japan

[ ⁵ ] Department of Neurosurgery Eiju General Hospital Tokyo Japan

[ ⁶ ] Department of Neurosurgery Jikei University Hospital Tokyo Japan

Author notes

[*] [* ] Correspondence

Hikaru Sasaki, Department of Neurosurgery, Keio University Hospital, Tokyo, Japan.

Email: hsasaki@ 123456keio.jp

and

Toshihide Tanaka, Department of Neurosurgery, Jikei University Kashiwa Hospital, Chiba, Japan.

Email: ttanaka@ 123456jikei.ac.jp

Author information

Hikaru Sasaki https://orcid.org/0000-0001-7380-1931

Article

Publisher ID: CAS13889

DOI: 10.1111/cas.13889

PMC ID: 6361613

PubMed ID: 30467920

SO-VID: 4db2e10b-5053-4f4d-a707-ee77cb1bf0d2

License:

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.

History

Date received : 08 August 2018

Date revision received : 06 November 2018

Date accepted : 19 November 2018

Page count

Figures: 4, Tables: 0, Pages: 10, Words: 6232

Funding

Funded by: Ministry of Education, Culture, Sports, Science and Technology and the Japan Society for the Promotion of Science (KAKENHI)

Custom metadata

source-schema-version-number 2.0

component-id cas13889

cover-date February 2019

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.8 mode:remove_FC converted:04.02.2019

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: bevacizumab,pd‐1,pd‐l1,tam,treg

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: bevacizumab, pd‐1, pd‐l1, tam, treg

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