Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade

Abstract

Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

Discordant humoral and cellular immune responses toCytomegalovirus(CMV) in glioblastoma patients whose tumors are positive for CMV

“…With current standard therapy, median overall survival (OS) for GBM patients is less than 15 mo after diagnosis. 1,2 An active HCMV infection, as determined by HCMV protein expression, can be detected in tumor cells in 90-100% of GBM patients; [3][4][5][6][7][8] however, the infection is absent in healthy surrounding tissues, indicating a potential oncomodulatory or oncogenic role of HCMV. We found that the median OS of GBM patients correlates with the grade of HCMV infection in tumor tissue.…”

Cytomegalovirus and glioblastoma; controversies and opportunities

“…Higher CMV levels have also been suggested to be correlated with poorer patient survival [6]. Human CMV pp65 was reported to be detected by another group in all brain tumors independent of type of grade [7]. CMV in tumors has also been detected in other tumor types in recent years, including breast cancer and metastases [26], medulloblastoma [27] and rhabdomyosarcoma [25].…”

“…Since the initial study by Cobbs et al [3] reporting the identification of CMV antigens and nucleic acids in glioblastoma patients, there have been numerous additional independent studies, which have confirmed and built on these findings [e.g., [4][5][6][7][8][9]. One study performed optimization of immunohistochemical techniques and was able to detect CMV IE1 in 100 % of glioblastomas and 82 % of low grade glioma [5].…”

“…In glioblastoma, although there is no viral cause known, cytomegalovirus (CMV) has become increasingly prominent in the field as CMV antigens and nucleic acids have been detected in glioblastoma by multiple research groups [3][4][5][6][7][8][9]. Many CMV gene products have tumor promoting effects, it has been shown that perinatal CMV infection promotes glioma progression in a mouse genetic model [10], and therapies directed against CMV including antiviral agents and immune approaches are now being examined in the clinic [11].…”

The role of CMV in glioblastoma and implications for immunotherapeutic strategies

“…More recent studies utilizing IHC have found pp65 positivity in gliomas, medulloblastomas, CNS lymphoma and meningiomas. 21 Others have found that 25% of patients with GBM had detectable levels of a CMV micro RNA (miR-UL112-3p) in their blood. 22 (Table 1)…”