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The Immunology and Biology of Brain Tumors
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The Immunology and Biology of Brain Tumors

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 20771

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Michael Graner

E-Mail Website
Guest Editor
Department Neurosurgery, University of Colorado Denver, Anschutz Medecal Campus, Aurora, CO 80045, USA
Interests: targeted immunotherapy of cancer; immunosuppression; exosome biology

Special Issue Information

Dear Colleagues,

We welcome your contributions to this Special Issue entitled “The Immunology and Biology of Brain Tumors”. Immunotherapy has become a viable treatment modality for a variety of cancers (and referred to as Science Magazine’s “Breakthrough of the Year” in 2013, as well as ASCO’s “Advance of the Year” in both 2016 and 2017). This Special Issue will focus on the relevance of immunobiology in brain tumors, touching on elements of immune suppression, immune stimulation, the immune microenvironment, with culminations in translational immunotherapy. Topics include, but are not limited to:

History of Brain Tumor Immunotherapy
Immune Checkpoints
Immune Checkpoint Inhibitors
Immune Suppression
            - by the tumor microenvironment
            - by tumor-release factors
            - in peripheral compartments
            - regulatory T cells
            - MDSCs
Immune Stimulation
Inflammation
Vaccines
            - DC-based
            - proteins
            - nucleic acids
            - cellular
            - nanomaterials
Immune Transfer
            - adoptive T cells
            - CAR-T cells
            - serologic
            - antibodies and constructs
Combination Therapies
Animal Models
Companion Animals

Journal of Clinical Medicine (ISSN 2077-0383; CODEN: JCMOHK) is an international, open access journal published monthly online by MDPI. It is indexed in the Science Citation Index Expanded (SCIE) in Web of Science and other databases. Citations become available in PubMed, with full-text archived in PubMed Central.

Prof. Michael Graner
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Clinical Medicine is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • History of Brain Tumor Immunotherapy
  • Immune Checkpoints
  • Immune Checkpoint Inhibitors
  • Immune Suppression
  • Immune Stimulation
  • Inflammation
  • Vaccines
  • Immune Transfer
  • Combination Therapies
  • Animal Models
  • Companion Animals

Published Papers (6 papers)

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Research

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9 pages, 851 KiB  
Article
Adrenal Insufficiency in Patients with Corticosteroid-Refractory Cerebral Radiation Necrosis Treated with Bevacizumab
by Martin Voss, AbdulAziz Batarfi, Eike Steidl, Marlies Wagner, Marie-Thérèse Forster, Joachim P. Steinbach, Claus M. Rödel, Jörg Bojunga and Michael W. Ronellenfitsch
J. Clin. Med. 2019, 8(10), 1608; https://doi.org/10.3390/jcm8101608 - 03 Oct 2019
Cited by 2 | Viewed by 2477
Abstract
Cerebral radiation necrosis is a common complication of the radiotherapy of brain tumours that can cause significant mortality. Corticosteroids are the standard of care, but their efficacy is limited and the consequences of long-term steroid therapy are problematic, including the risk of adrenal [...] Read more.
Cerebral radiation necrosis is a common complication of the radiotherapy of brain tumours that can cause significant mortality. Corticosteroids are the standard of care, but their efficacy is limited and the consequences of long-term steroid therapy are problematic, including the risk of adrenal insufficiency (AI). Off-label treatment with the vascular endothelial growth factor A antibody bevacizumab is highly effective in steroid-resistant radiation necrosis. Both the preservation of neural tissue integrity and the cessation of steroid therapy are key goals of bevacizumab treatment. However, the withdrawal of steroids may be impossible in patients who develop AI. In order to elucidate the frequency of AI in patients with cerebral radiation necrosis after treatment with corticosteroids and bevacizumab, we performed a retrospective study at our institution’s brain tumour centre. We obtained data on the tumour histology, age, duration and maximum dose of dexamethasone, radiologic response to bevacizumab, serum cortisol, and the need for hydrocortisone substitution for AI. We identified 17 patients with cerebral radiation necrosis who had received treatment with bevacizumab and had at least one available cortisol analysis. Fifteen patients (88%) had a radiologic response to bevacizumab. Five of the 17 patients (29%) fulfilled criteria for AI and required hormone substitution. Age, duration of dexamethasone treatment, and time since radiation were not statistically associated with the development of AI. In summary, despite the highly effective treatment of cerebral radiation necrosis with bevacizumab, steroids could yet not be discontinued due to the development of AI in roughly one-third of patients. Vigilance to spot the clinical and laboratory signs of AI and appropriate testing and management are, therefore, mandated. Full article
(This article belongs to the Special Issue The Immunology and Biology of Brain Tumors)
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12 pages, 1750 KiB  
Article
Biopsy Confirmed Glioma Recurrence Predicted by Multi-Modal Neuroimaging Metrics
by Jamie D. Costabile, John A. Thompson, Elsa Alaswad and D. Ryan Ormond
J. Clin. Med. 2019, 8(9), 1287; https://doi.org/10.3390/jcm8091287 - 23 Aug 2019
Cited by 5 | Viewed by 2318
Abstract
Histopathological verification is currently required to differentiate tumor recurrence from treatment effects related to adjuvant therapy in patients with glioma. To bypass the complications associated with collecting neural tissue samples, non-invasive classification methods are needed to alleviate the burden on patients while providing [...] Read more.
Histopathological verification is currently required to differentiate tumor recurrence from treatment effects related to adjuvant therapy in patients with glioma. To bypass the complications associated with collecting neural tissue samples, non-invasive classification methods are needed to alleviate the burden on patients while providing vital information to clinicians. However, uncertainty remains as to which tissue features on magnetic resonance imaging (MRI) are useful. The primary objective of this study was to quantitatively assess the reliability of combining MRI and diffusion tensor imaging metrics to discriminate between tumor recurrence and treatment effects in histopathologically identified biopsy samples. Additionally, this study investigates the noise adjuvant radiation therapy introduces when discriminating between tissue types. In a sample of 41 biopsy specimens, from a total of 10 patients, we derived region-of-interest samples from MRI data in the ipsilateral hemisphere that encompassed biopsies obtained during resective surgery. This study compares normalized intensity values across histopathology classifications and contralesional volumes reflected across the midline. Radiation makes noninvasive differentiation of abnormal-nontumor tissue to tumor recurrence much more difficult. This is because radiation exhibits opposing behavior on key MRI modalities: specifically, on post-contrast T1, FLAIR, and GFA. While radiation makes noninvasive differentiation of tumor recurrence more difficult, using a novel analysis of combined MRI metrics combined with clinical annotation and histopathological correlation, we observed that it is possible to successfully differentiate tumor tissue from other tissue types. Additional work will be required to expand upon these findings. Full article
(This article belongs to the Special Issue The Immunology and Biology of Brain Tumors)
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16 pages, 3305 KiB  
Article
Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages
by Hao-Yu Chuang, Yu-kai Su, Heng-Wei Liu, Chao-Hsuan Chen, Shao-Chih Chiu, Der-Yang Cho, Shinn-Zong Lin, Yueh-Sheng Chen and Chien-Min Lin
J. Clin. Med. 2019, 8(7), 959; https://doi.org/10.3390/jcm8070959 - 02 Jul 2019
Cited by 64 | Viewed by 5214
Abstract
Background: The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may [...] Read more.
Background: The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins, and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells’ resistance against temozolomide (TMZ) by upregulating the prosurvival gene programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2), signal transducer and activator of transcription 3 (STAT3), Nestin, and miR-21-5p and increasing the M2 cytokines interleukin 6 (IL-6) and transforming growth factor beta 1(TGF-β1) secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed a markedly reduced ability to secret M2 cytokines and reduced miR-21-enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and GAMs. Treatment with pacritinib and the combination of pacritinib and TMZ appeared to significantly reduce the tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of GAMs. Conclusion: In summation, we showed the potential of pacritinib alone or in combination with TMZ to suppress GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in clinical settings. Full article
(This article belongs to the Special Issue The Immunology and Biology of Brain Tumors)
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12 pages, 11011 KiB  
Article
Analysis of Tumor Angiogenesis and Immune Microenvironment in Non-Functional Pituitary Endocrine Tumors
by Mizuto Sato, Ryota Tamura, Haruka Tamura, Taro Mase, Kenzo Kosugi, Yukina Morimoto, Kazunari Yoshida and Masahiro Toda
J. Clin. Med. 2019, 8(5), 695; https://doi.org/10.3390/jcm8050695 - 16 May 2019
Cited by 53 | Viewed by 3617
Abstract
Cavernous sinus (CS) invasion is an aggressive behavior exhibited by pituitary neuroendocrine tumors (PitNETs). The cause of CS invasion in PitNETs has not been fully elucidated. The tumor immune microenvironment, known to promote aggressive behavior in various types of tumors, has not been [...] Read more.
Cavernous sinus (CS) invasion is an aggressive behavior exhibited by pituitary neuroendocrine tumors (PitNETs). The cause of CS invasion in PitNETs has not been fully elucidated. The tumor immune microenvironment, known to promote aggressive behavior in various types of tumors, has not been examined for PitNETs. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) signaling is strongly associated with the tumor immune microenvironment. In the present study, these molecular and histopathological characteristics were examined in invasive non-functional PitNETs (NF-PitNETs). Twenty-seven patients with newly diagnosed NF-PitNETs (with CS invasion: 17, without CS invasion: 10) were analyzed by immunohistochemistry for VEGF-A/VEGFR1 and 2, hypoxia-inducible Factor (HIF), tumor-infiltrating lymphocytes, immunosuppressive cells including regulatory T cells (Tregs) and tumor-associated macrophages (TAMs), and immune checkpoint molecules. Previously validated tumor proliferation markers including mitotic count, Ki-67 index, and p53 were also analyzed for their expressions in NF-PitNETs. VEGF-A and VEGFR1 were expressed on not only vascular endothelial cells, but also on tumor cells. The expressions of VEGF-A and VEGFR1 were significantly higher in NF-PitNETs with CS invasion. The number of TAMs and the expression of PD-L1 were also significantly higher in NF-PitNETs with CS invasion than in NF-PitNETs without CS invasion. The high expression of VEGF-A and VEGFR1 and associated immunosuppressive microenvironment were observed in NF-PitNETs with CS invasion, suggesting that a novel targeted therapy can be applied. Full article
(This article belongs to the Special Issue The Immunology and Biology of Brain Tumors)
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12 pages, 1199 KiB  
Article
A Pilot Study of Vaccine Therapy with Multiple Glioma Oncoantigen/Glioma Angiogenesis-Associated Antigen Peptides for Patients with Recurrent/Progressive High-Grade Glioma
by Ryogo Kikuchi, Ryo Ueda, Katsuya Saito, Shunsuke Shibao, Hideaki Nagashima, Ryota Tamura, Yukina Morimoto, Hikaru Sasaki, Shinobu Noji, Yutaka Kawakami, Kazunari Yoshida and Masahiro Toda
J. Clin. Med. 2019, 8(2), 263; https://doi.org/10.3390/jcm8020263 - 20 Feb 2019
Cited by 16 | Viewed by 3425
Abstract
High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we [...] Read more.
High-grade gliomas (HGGs) carry a dismal prognosis despite current treatments. We previously confirmed the safety and immunogenicity of a vaccine treatment targeting tumor angiogenesis with synthetic peptides, for vascular endothelial growth factor receptor (VEGFR) epitopes in recurrent HGG patients. In this study, we evaluated a novel vaccine therapy targeting not only tumor vasculature but also tumor cells, using multiple glioma oncoantigen (GOA)/glioma angiogenesis-associated antigen (GAAA) peptides in HLA-A2402+ recurrent/progressive HGG patients. The vaccine included peptide epitopes from four GOAs (LY6K, DEPDC1, KIF20A, and FOXM1) and two GAAAs (VEGFR1 and VEGFR2). Ten patients received subcutaneous vaccinations. The primary endpoint was the safety of the treatment. T-lymphocyte responses against GOA/GAAA epitopes and treatment response were evaluated secondarily. The treatment was well tolerated without any severe systemic adverse events. The vaccinations induced immunoreactivity to at least three vaccine-targeted GOA/GAAA in all six evaluable patients. The median overall survival time in all patients was 9.2 months. Five achieved progression-free status lasting at least six months. Two recurrent glioblastoma patients demonstrated stable disease. One patient with anaplastic oligoastrocytoma achieved complete response nine months after the vaccination. Taken together, this regimen was well tolerated and induced robust GOA/GAAA-specific T-lymphocyte responses in recurrent/progressive HGG patients. Full article
(This article belongs to the Special Issue The Immunology and Biology of Brain Tumors)
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Review

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13 pages, 2475 KiB  
Review
The Inflammatory Milieu of Adamantinomatous Craniopharyngioma and Its Implications for Treatment
by Ros Whelan, Eric Prince, Ahmed Gilani and Todd Hankinson
J. Clin. Med. 2020, 9(2), 519; https://doi.org/10.3390/jcm9020519 - 14 Feb 2020
Cited by 25 | Viewed by 3224
Abstract
Pediatric Adamantinomatous Craniopharyngiomas (ACPs) are histologically benign brain tumors that often follow an aggressive clinical course. Their suprasellar location leaves them in close proximity to critical neurological and vascular structures and often results in significant neuroendocrine morbidity. Current treatment paradigms, involving surgical resection [...] Read more.
Pediatric Adamantinomatous Craniopharyngiomas (ACPs) are histologically benign brain tumors that often follow an aggressive clinical course. Their suprasellar location leaves them in close proximity to critical neurological and vascular structures and often results in significant neuroendocrine morbidity. Current treatment paradigms, involving surgical resection and radiotherapy, confer significant morbidity to patients and there is an obvious need to discover effective and safe alternative treatments. Recent years have witnessed significant efforts to fully detail the genomic, transcriptomic and proteomic make-up of these tumors, in an attempt to identify potential therapeutic targets. These studies have resulted in ever mounting evidence that inflammatory processes and the immune response play a critical role in the pathogenesis of both the solid and cystic portion of ACPs. Several inflammatory and immune markers have been identified in both the cyst fluid and solid tumor tissue of ACP. Due to the existence of effective agents that target them, IL-6 and immune checkpoint inhibitors seem to present the most likely immediate candidates for clinical trials of targeted immune-related therapy in ACP. If effective, such agents may result in a paradigm shift in treatment that ultimately reduces morbidity and results in better outcomes for our patients. Full article
(This article belongs to the Special Issue The Immunology and Biology of Brain Tumors)
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