Detection of human cytomegalovirus in glioblastoma among Taiwanese subjects

Yang, Ching‐Fen; Ho, Hsiang‐Ling; Lin, Shih‐Chieh; Hsu, Chih‐Yi; Ho, Donald Ming‐Tak

doi:10.1371/journal.pone.0179366

Cited by 17 publications

(20 citation statements)

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“…However, this link between CMV and tumor progression is far from clear. Several clinical studies have failed to identify HCMV in human tumors, even with the use of very sensitive molecular techniques (54)(55)(56)(57). Moreover, several studies suggest that CMV may have the opposite effect and block tumor growth in other experimental situations.…”

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confidence: 99%

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

Wilski

Casale

Purwin

et al. 2019

J Virol

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Cytomegalovirus (CMV) is a ubiquitous betaherpesvirus that infects many different cell types. Human CMV (HCMV) has been found in several solid tumors, and it has been hypothesized that it may promote cellular transformation or exacerbate tumor growth. Paradoxically, in some experimental situations, murine CMV (MCMV) infection delays tumor growth. We previously showed that wild-type MCMV delayed the growth of poorly immunogenic B16 melanomas via an undefined mechanism. Here, we show that MCMV delayed the growth of these immunologically “cold” tumors by recruiting and modulating tumor-associated macrophages. Depletion of monocytic phagocytes with clodronate completely prevented MCMV from delaying tumor growth. Mechanistically, our data suggest that MCMV recruits new macrophages to the tumor via the virus-encoded chemokine MCK2, and viruses lacking this chemokine were unable to delay tumor growth. Moreover, MCMV infection of macrophages drove them toward a proinflammatory (M1)-like state. Importantly, adaptive immune responses were also necessary for MCMV to delay tumor growth as the effect was substantially blunted in Rag-deficient animals. However, viral spread was not needed and a spread-defective MCMV strain was equally effective. In most mice, the antitumor effect of MCMV was transient. Although the recruited macrophages persisted, tumor regrowth correlated with a loss of viral activity in the tumor. However, an additional round of MCMV infection further delayed tumor growth, suggesting that tumor growth delay was dependent on active viral infection. Together, our results suggest that MCMV infection delayed the growth of an immunologically cold tumor by recruiting and modulating macrophages in order to promote anti-tumor immune responses. IMPORTANCE Cytomegalovirus (CMV) is an exciting new platform for vaccines and cancer therapy. Although CMV may delay tumor growth in some settings, there is also evidence that CMV may promote cancer development and progression. Thus, defining the impact of CMV on tumors is critical. Using a mouse model of melanoma, we previously found that murine CMV (MCMV) delayed tumor growth and activated tumor-specific immunity although the mechanism was unclear. We now show that MCMV delayed tumor growth through a mechanism that required monocytic phagocytes and a viral chemokine that recruited macrophages to the tumor. Furthermore, MCMV infection altered the functional state of macrophages. Although the effects of MCMV on tumor growth were transient, we found that repeated MCMV injections sustained the antitumor effect, suggesting that active viral infection was needed. Thus, MCMV altered tumor growth by actively recruiting macrophages to the tumor, where they were modulated to promote antitumor immunity.

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confidence: 99%

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

Wilski

Casale

Purwin

et al. 2019

J Virol

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“…Literatures that met the following criteria were excluded: (1) the written language was not English, (2) reviews, letters, editorials, and meeting records, (3) study focusing on gene expression, (4) the detection samples were not from the glioma samples of the patients, (5) neither the viral antigen nor DNA were detected, and (6) sample cases were from a database.…”

Section: Eligibility Criteria and Quality Assessmentmentioning

confidence: 99%

“…2018)[4],(Yang et al 2017)[5],(Bahador et al 2017)[6],(Ding et al 2014)[7], (Rahbar et al 2013)[8], and (Rahbar, a. et al 2012)[9] ; 2 studies involved HPV: (Adnan Ali et al 2019)[10], (Vidone et al 2014)[11] and (Wang et al 2017)[14]; 2 studies involved HHV-6: (Crawford et al 2009)[12] and[13]; and 1 study involved SV40, WMSV and HERV-K113:(Wang et al 2017) …”

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confidence: 99%

Viral infection and glioma: a meta-analysis of prognosis.

Cai

Yang

et al. 2020

Preprint

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Background: Glioma is the most common primary brain tumor, occurring due to the carcinogenesis of glial cells in the brain and spinal cord. Many aspects of the mechanism of its tumorigenesis remain unknown. The relationship between viral infection and glioma is one of the most important research aspects in this field. Currently, there is a lack of systematic reviews and meta-analyses to evaluate the effect of viral infection on the prognosis of glioma patients. The purpose of this study was to evaluate the relationship between viral infection and the prognosis of glioma patients, aimed at evaluating the prognostic value of the detection of viral infection.Methods: Through careful and comprehensive retrieval of results from the PubMed, Embase, and Cochrane databases, eligible articles were selected strictly according to the inclusion and exclusion criteria. The regional sources, detection methods, detection indicators, patient survival, and other data from the samples in the papers were extracted, and the integrated analysis was conducted using Stata 15.1. We conducted a subgroup analysis of the relationship between the degree of infection and prognosis in cytomegalovirus (CMV) patients.Results: A total of 11 studies were included in the analysis. Among them, 7 studies involved the relationship between CMV infection and the prognosis of patients with glioma, 2 studies involved human papillomavirus (HPV), 2 studies involved human herpesvirus-6 (HHV-6), and one study involved simian virus 40 (SV40), woolly monkey sarcoma virus (WMSV) and human endogenous retrovirus K113 (HERV-K113). In the CMV study, the pooled Hazard ratio (HR) of Overall survival (OS) was 1.024 (CI: 0.698–1.501), with a P value of 0.905. The pooled HR of Progression free survival (PFS) was 1.067 (CI: 0.770–1.478), with a P value of 0.697. The pooled HR value of low-degree infection versus high-degree infection was 1.476 (CI: 0.799–2.727), with a P value of 0.213. In the HPV study, the pooled HR of OS was 1.467 (CI: 0.552–3.901), with a P value of 0.443.Conclusion: CMV infection has no significant effect on the prognosis of glioma patients. Using the IEA as the detection index, the degree of CMV infection was found to have a significant impact on the prognosis of glioma patients; it was not found to possess a significant prognostic value after the integration of different indicators. Neither HPV nor HHV-6 infection has a significant effect on the prognosis of glioma patients. SV40 and WMSV infection are associated with poor prognosis in patients with low-grade glioma.Registration: this meta-analysis registered in https://www.crd.york.ac.uk/PROSPERO/, PROSPERO ID: CRD42019127648.

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“…No viral detection by day 7 post-challenge in brains and lungs (HA)-MCMV IVL [35] IN route induced lung CD8 TRM accumulation IAV PR8M variant IN challenge MHC-I restricted peptide IVL [533][534][535][536][537][538][539][540][541] Inserted into the C-terminus of the ie2 IN reduced lung viral load and weight loss at a higher magnitude than IP route MCMV ie2E6/E7Full [14] Protective CD8 T cells Heterotopic (subcutaneous) administration of TC-1 cells transformed with HPV16 E6 and E7-oncogenes cells [59] and subsequent development of an immunosuppressive microenvironment [60] partially overlap with phenomena promoting the immune evasion by cancer cells [61]. Some clinical studies have suggested a role for CMV in the pathogenesis of glioblastoma, an aggressive neoplasm of the central nervous system [62,63] but subsequent studies have shown conflicting results concerning HCMV identification in tumours [64][65][66][67][68], a fundamental requisite according to the criteria proposed by Frederick and Relman for the identification of diseases caused by viruses [69,70]. Therefore, a consensus to consider CMV as an oncogenic virus or merely an oncomodulatory virus that may cause tumour cells to become more aggressive has not been reached [71].…”

Section: Mouse-adapted Zebov Ip Challengementioning

confidence: 99%

“…Advantages of using a full-length protein include the elicitation of broad immune responses in various MHC backgrounds which increases the prospect of a protective response toward critical epitopes in genetically heterogeneous populations [149]. A comparison of MCMV-based vectors encoding either the full length gene of the prostate-specific antigen (PSA) (MCMV/PSA FL ) or a PSA-derived epitope (MCMV/PSA [65][66][67][68][69][70][71][72][73] ) within the ie2 gene [150] showed that only MCMV/PSA [65][66][67][68][69][70][71][72][73] protected against tumour challenge with a PSA-expressing adenocarcinoma, although both vectors induced an inflationary response of PSA-specific CD8 T cells. As MCMV/PSA FL induced poor CD8 response upon challenge, the mechanism of CD8 suppression was suspected to depend on differences in the functionality of responding cells.…”

Section: Cellular Response-t Cellsmentioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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Detection of human cytomegalovirus in glioblastoma among Taiwanese subjects

Cited by 17 publications

References 50 publications

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

Viral infection and glioma: a meta-analysis of prognosis.

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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