Consensus on the role of human cytomegalovirus in glioblastoma

Abstract

The human cytomegalovirus (HCMV) and glioma symposium was convened on April 17, 2011 in Washington, DC, and was attended by oncologists and virologists involved in studying the relationship between HCMV and gliomas. The purpose of the meeting was to reach a consensus on the role of HCMV in the pathology of gliomas and to clarify directions for future research. First, the group summarized data that describe how HCMV biology overlaps with the key pathways of cancer. Then, on the basis of published data and ongoing research, a consensus was reached that there is sufficient evidence to conclude that HCMV sequences and viral gene expression exist in most, if not all, malignant gliomas, that HCMV could modulate the malignant phenotype in glioblastomas by interacting with key signaling pathways; and that HCMV could serve as a novel target for a variety of therapeutic strategies. In summary, existing evidence supports an oncomodulatory role for HCMV in malignant gliomas, but future studies need to focus on determining the role of HCMV as a glioma-initiating event.

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

“…This publication established that CMV is expressed in most human glioma samples with sensitive assays. 23 Peripheral blood tests do not always correlate with CMV positivity in tumor samples. Controversy remains about the role of CMV in glioma oncogenesis.…”

Advances in the Treatment of Primary Brain Tumors: The Realm of Immunotherapy

“…Since that time, there has been much controversy surround this topic with a high degree of variability in the literature regarding the detection of HCMV in CNS tumors . To help resolve some of this controversy, a consensus paper was published in 2012 [93]. Despite this, a consensus paper stating the existence of HCMV in gliomas and their potential role in tumorigenesis, recent studies using next-generation sequencing have not been able to identify any HCMV in CNS tumor tissue [73, 81, 85-87, 92, 93].…”

Human cytomegalovirus-based immunotherapy to treat glioblastoma: Into the future

“…3 The fact that HCMV is absent in healthy tissue, but found in 75-100% of various grade gliomas, makes it an attractive target candidate for HCMV-specific cytotoxic (CD8 C ) T cells. 4 Interestingly, recent studies showed that HCMV has a higher infection efficiency in GBM SLC compared to other glioma cell lines, and HCVM infection can even induce a SLC phenotype in GBM tumor cells. 5 As GBM is a highly heterogeneous tumor, a single antigenic target is likely insufficient.…”

“…Tumor cells produce CCL2, thereby recruiting both regulatory T cells (Treg) and tumor-associated macrophages (TAMs), which become immunosuppressive under the influence of hypoxia induced factor-1a (HIF-1a) and cytokines such as IL-6 and viral IL-10. 4 TAMs produce multiple anti-inflammatory cytokines, such as IL-10 and TGFb, which inhibit effector T cells. Furthermore, HCMV immune evasive US peptides are able to negatively influence MHC I expression by increasing proteasomal degradation of the MHC heavy chain (US2, 10, 11) and retention of the whole MHC complex in the ER (US3).…”

“…While the activating receptor CD94/NKG2C also recognizes the UL40 HLA-E binding epitope, though with very low affinity, UL40 mainly induces inhibition of NK cells, thereby protecting HCMV infected cells from lysis. 4 Although GBM also has increased HLA-E expression, it is unclear whether this is induced by the presence of HCMV. Another contributor is programmed cell death ligand-1 (PD-L1) expressed in over 80% of glioblastomas, although not directly linked to HCMV, it is correlated with malignancy of gliomas.…”