bims-malgli 2021-11-21 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2021–11–21
six papers selected by
Oltea Sampetrean, Keio University

An overview of current therapeutic strategies for glioblastoma and the role of CD73 as an alternative curative approach.
Spatiotemporal dynamics of a glioma immune interaction model.
For whom the T cells troll? Bispecific T-cell engagers in glioblastoma.
Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.
CPVL promotes glioma progression via STAT1 pathway inhibition through interactions with the BTK/p300 axis.
T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas.

Clin Transl Oncol. 2021 Nov 18.

An overview of current therapeutic strategies for glioblastoma and the role of CD73 as an alternative curative approach.

S Arab, F Hasannejad.

  Glioblastoma multiforme (GBM) is a complicated and heterogeneous brain tumor with short-term survival outcomes. Commercial therapies are not practical due to cell infiltration capacity, high proliferative rate, and blood-brain barrier. In this context, recognition of the molecular mechanism of tumor progression might help the development of new cancer therapeutics. Recently, more evidence has supported CD73 and downstream adenosine A2A/A2B receptor signaling playing a crucial role in glioblastoma pathogenesis; therefore, targeting CD73 in murine tumor models can reduce tumor development. CD73 is an ecto-enzyme inducing tumor metastasis, angiogenesis, and immune escape via the production of extracellular adenosine in the tumor microenvironment. In this review, we provided information about clinical characteristics as well as the therapeutic management of glioblastoma. Then, we focused on newly available experimental evidence distinguishing between the essential role of CD73 on this tumor growth and a new method for the treatment of GBM patients.

Keywords:  Adenosine; Brain cancer; CD73; Glioblastoma; Hypoxia

DOI:  https://doi.org/10.1007/s12094-021-02732-4
Sci Rep. 2021 Nov 17. 11(1): 22385

Spatiotemporal dynamics of a glioma immune interaction model.

Subhas Khajanchi, Juan J Nieto.

We report a mathematical model which depicts the spatiotemporal dynamics of glioma cells, macrophages, cytotoxic-T-lymphocytes, immuno-suppressive cytokine TGF-β and immuno-stimulatory cytokine IFN-γ through a system of five coupled reaction-diffusion equations. We performed local stability analysis of the biologically based mathematical model for the growth of glioma cell population and their environment. The presented stability analysis of the model system demonstrates that the temporally stable positive interior steady state remains stable under the small inhomogeneous spatiotemporal perturbations. The irregular spatiotemporal dynamics of gliomas, macrophages and cytotoxic T-lymphocytes are discussed extensively and some numerical simulations are presented. Performed some numerical simulations in both one and two dimensional spaces. The occurrence of heterogeneous pattern formation of the system has both biological and mathematical implications and the concepts of glioma cell progression and invasion are considered. Simulation of the model shows that by increasing the value of time, the glioma cell population, macrophages and cytotoxic-T-lymphocytes spread throughout the domain.

DOI: https://doi.org/10.1038/s41598-021-00985-1
J Immunother Cancer. 2021 Nov;pii: e003679. [Epub ahead of print]9(11):

For whom the T cells troll? Bispecific T-cell engagers in glioblastoma.

Kirit Singh, Kelly M Hotchkiss, Aditya A Mohan, Jessica L Reedy, John H Sampson, Mustafa Khasraw.

  Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood-brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.

Keywords:  T lymphocytes; central nervous system neoplasms; immunotherapy

DOI:  https://doi.org/10.1136/jitc-2021-003679
Lab Invest. 2021 Nov 15.

Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.

James A Innes, Andrew S Lowe, Raquel Fonseca, Natasha Aley, Tedani El-Hassan, Myrianni Constantinou, Joanne Lau, Ayad Eddaoudi, Silvia Marino, Sebastian Brandner.

The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities.

DOI: https://doi.org/10.1038/s41374-021-00695-2
JCI Insight. 2021 Nov 16. pii: e146362. [Epub ahead of print]

CPVL promotes glioma progression via STAT1 pathway inhibition through interactions with the BTK/p300 axis.

Hui Yang, Xiaocen Liu, Xiaolong Zhu, Xueqin Li, Lan Jiang, Min Zhong, Mengying Zhang, Tianbing Chen, Mingzhe Ma, Xiuming Liang, Kun Lv.

  CPVL (Carboxypeptidase, vitellogenic-like) is a serine carboxypeptidase which was first characterized in human macrophages. However, the function of CPVL remains unclear in a variety of tumors. The quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and immunohistochemistry (IHC) assays were utilized to measure the CPVL expression. CPVL was signiﬁcantly upregulated in glioma cells and tissues compared to normal cells and tissues, respectively. Moreover, high CPVL expression was correlated with advanced clinical grade and poor prognosis. Silencing of CPVL promoted glioma cell apoptosis, inhibited cell proliferation and tumorigenicity in vitro and in vivo. Ingenuity Pathway Analysis (IPA) demonstrated that CPVL silencing activated the IFN-γ/STAT1 signaling pathway, thereby inducing glioma cell apoptosis. Mechnistically, immunopurification, mass spectrometry, immunoprecipitation (IP), and glutathione S-transferase (GST) pull-down experiments elucidated that CPVL physically interacts with Bruton's tyrosine kinase (BTK) and downregulates the STAT1 phosphorylation through promoting p300-mediated STAT1 acetylation. For the first time, our findings revealed the crucial role of CPVL in promoting the progression of glioma through suppressing STAT1 phosphorylation. CPVL might serve as a potential prognostic biomarker and therapeutic target for the treatment of glioma.

Keywords:  Oncogenes; Oncology

DOI:  https://doi.org/10.1172/jci.insight.146362
Clin Cancer Res. 2021 Nov 15. pii: clincanres.1881.2021. [Epub ahead of print]

T cell receptor therapy targeting mutant capicua transcriptional repressor in experimental gliomas.

Michael Kilian, Mirco Friedrich, Khwab Sanghvi, Edward Green, Stefan Pusch, Daisuke Kawauchi, Martin Löwer, Jana K Sonner, Christopher Krämer, Julia Zaman, Stefanie Jung, Michael O Breckwoldt, Gerald Willimksy, Stefan B Eichmüller, Andreas von Deimling, Wolfgang Wick, Felix Sahm, Michael Platten, Lukas Bunse.

PURPOSE: Gliomas are intrinsic brain tumors with a high degree of constitutive and acquired resistance to standard therapeutic modalities such as radiotherapy and alkylating chemotherapy. Glioma subtypes are recognized by characteristic mutations. Some of these characteristic mutations have shown to generate immunogenic neoepitopes suitable for targeted immunotherapy.
EXPERIMENTAL DESIGN: Using peptide-based ELISpot assays, we screened for potential recurrent glioma neoepitopes in MHC-humanized mice. Following vaccination, droplet-based single cell T cell receptor (TCR) sequencing from established T cell lines was applied for neoepitope-specific TCR discovery. Efficacy of intraventricular TCR-transgenic T cell therapy was assessed in a newly developed glioma model in MHC-humanized mice induced by CRISPR-based delivery of tumor suppressor-targeting guide RNAs.
RESULTS: We identify recurrent capicua transcriptional repressor (CIC) inactivating hotspot mutations at position 215 CICR215W/Q as immunogenic major histocompatibility complex (MHC) class II-restricted neoepitopes. Vaccination of MHC-humanized mice resulted in the generation of robust MHC class II (MHCII)-restricted mutation-specific T cell responses against CICR215W/Q. Adoptive intraventricular transfer of CICR215W-specific TCR-transgenic T cells exert anti-tumor responses against CICR215W-expressing syngeneic gliomas.
CONCLUSION: The integration of immunocompetent MHC-humanized orthotopic glioma models in the discovery of shared immunogenic glioma neoepitopes facilitates the identification and preclinical testing of HLA-restricted neoepitope-specific TCRs for locoregional TCR-transgenic T cell adoptive therapy.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1881