The role of CMV in glioblastoma and implications for immunotherapeutic strategies

Rahman, Maryam; Dastmalchi, Farhad; Karachi, Aida; Mitchell, Duane A.

doi:10.1080/2162402x.2018.1514921

Cited by 52 publications

(53 citation statements)

References 70 publications

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“…HLA-G is not just expressed on the cell surface - a soluble isoform that is secreted has been detected in plasma, cerebrospinal fluid and seminal plasma. GBM tumors are frequently infected with cytomegalovirus (hCMV), and hCMV infection has been associated with high levels of HLA-G expression ( 60 ). Cytomegalovirus infection is prevalent in the population and infection is lifelong.…”

Section: Immune Inhibitory Proteins Expressed By Gbm Tumorsmentioning

confidence: 99%

“…Cytomegalovirus infection is prevalent in the population and infection is lifelong. The immunosuppression linked with GBM results in reduced control of hCMV and this results in reactivation of the virus ( 60 ). HLA-G can bind to several receptors, namely the inhibitory receptors Ig-Like Transcript 2 (ILT2) and Ig-Like Transcript 4 (ILT4) ( 61 ).…”

Section: Immune Inhibitory Proteins Expressed By Gbm Tumorsmentioning

confidence: 99%

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Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

et al. 2020

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Glioblastoma multiforme (GBM) is the most frequently occurring primary brain tumor and has a very poor prognosis, with only around 5% of patients surviving for a period of 5 years or more after diagnosis. Despite aggressive multimodal therapy, consisting mostly of a combination of surgery, radiotherapy, and temozolomide chemotherapy, tumors nearly always recur close to the site of resection. For the past 15 years, very little progress has been made with regards to improving patient survival. Although immunotherapy represents an attractive therapy modality due to the promising pre-clinical results observed, many of these potential immunotherapeutic approaches fail during clinical trials, and to date no immunotherapeutic treatments for GBM have been approved. As for many other difficult to treat cancers, GBM combines a lack of immunogenicity with few mutations and a highly immunosuppressive tumor microenvironment (TME). Unfortunately, both tumor and immune cells have been shown to contribute towards this immunosuppressive phenotype. In addition, current therapeutics also exacerbate this immunosuppression which might explain the failure of immunotherapy-based clinical trials in the GBM setting. Understanding how these mechanisms interact with one another, as well as how one can increase the anti-tumor immune response by addressing local immunosuppression will lead to better clinical results for immune-based therapeutics. Improving therapeutic delivery across the blood brain barrier also presents a challenge for immunotherapy and future therapies will need to consider this. This review highlights the immunosuppressive mechanisms employed by GBM cancers and examines potential immunotherapeutic treatments that can overcome these significant immunosuppressive hurdles.

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Section: Immune Inhibitory Proteins Expressed By Gbm Tumorsmentioning

confidence: 99%

Section: Immune Inhibitory Proteins Expressed By Gbm Tumorsmentioning

confidence: 99%

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

et al. 2020

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“…HCMV infection commonly causes acute infection in cancer patients undergoing immunosuppressive therapies for the treatment of leukemia, lymphoma, and myeloma (Kuo et al, 2008 ; El-Cheikh et al, 2013 ; Tay et al, 2013 ; Teh et al, 2013 ). Although controversial, it has also been associated with certain brain cancers including malignant glioma and medulloblastoma (Cobbs et al, 2002 , 2007 ; Baryawno et al, 2011 ; Soroceanu et al, 2011 ; Ranganathan et al, 2012 ; Rahman et al, 2019 ). Due to the immunosuppressive nature of the treatments used to fight various cancers, these cancer patient populations are highly susceptible to HCMV infection.…”

Section: Hcmv and Cancermentioning

confidence: 99%

Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

Dunn

Munger

2020

Front. Cell. Infect. Microbiol.

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Calcium signaling and the AMP-activated protein kinase (AMPK) signaling networks broadly regulate numerous aspects of cell biology. Human Cytomegalovirus (HCMV) infection has been found to actively manipulate the calcium-AMPK signaling axis to support infection. Many HCMV genes have been linked to modulating calcium signaling, and HCMV infection has been found to be reliant on calcium signaling and AMPK activation. Here, we focus on the cell biology of calcium and AMPK signaling and what is currently known about how HCMV modulates these pathways to support HCMV infection and potentially contribute to oncomodulation.

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“…This ability to change the TME makes them potentially powerful agents when concurrently used with other forms of immunotherapy, like checkpoint blockade [ 116 ]. Various types of oncolytic viruses are currently being studied, including herpes, poliovirus, adenovirus, cytomegalovirus (CMV), measles, coxsackie, parvovirus, and reovirus [ 113 , 117 , 118 , 119 ]. Historically, much work was done using herpes viruses as oncolytic therapy for malignant glioma [ 120 ].…”

Section: Enhancing the Adaptive Immune Response In Gbmmentioning

confidence: 99%

The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy

Desland

Hormigo

2020

IJMS

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Glioblastoma (GBM) is the most common and aggressive malignant primary brain tumor in adults. Its aggressive nature is attributed partly to its deeply invasive margins, its molecular and cellular heterogeneity, and uniquely tolerant site of origin—the brain. The immunosuppressive central nervous system (CNS) and GBM microenvironments are significant obstacles to generating an effective and long-lasting anti-tumoral response, as evidenced by this tumor’s reduced rate of treatment response and high probability of recurrence. Immunotherapy has revolutionized patients’ outcomes across many cancers and may open new avenues for patients with GBM. There is now a range of immunotherapeutic strategies being tested in patients with GBM that target both the innate and adaptive immune compartment. These strategies include antibodies that re-educate tumor macrophages, vaccines that introduce tumor-specific dendritic cells, checkpoint molecule inhibition, engineered T cells, and proteins that help T cells engage directly with tumor cells. Despite this, there is still much ground to be gained in improving the response rates of the various immunotherapies currently being trialed. Through historical and contemporary studies, we examine the fundamentals of CNS immunity that shape how to approach immune modulation in GBM, including the now revamped concept of CNS privilege. We also discuss the preclinical models used to study GBM progression and immunity. Lastly, we discuss the immunotherapeutic strategies currently being studied to help overcome the hurdles of the blood–brain barrier and the immunosuppressive tumor microenvironment.

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The role of CMV in glioblastoma and implications for immunotherapeutic strategies

Cited by 52 publications

References 70 publications

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

Immune Escape in Glioblastoma Multiforme and the Adaptation of Immunotherapies for Treatment

Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy

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