Epstein–Barr virus-encoded LMP1 induces ectopic CD137 expression on Hodgkin and Reed–Sternberg cells via the PI3K-AKT-mTOR pathway

Aravinth, Sneha Priya; Rajendran, Sakthi; Li, Yating; Wu, Meihui; Wong, Hiu Yi; Schwarz, Herbert

doi:10.1080/10428194.2019.1607330

Cited by 25 publications

(24 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…EBV proteins can be detected in most HL cases, especially in developing countries. 12 Finally, our group found 96% of the CD137 + HRS cells being positive for LMP1, and 72% LMP1 + HRS cells being positive for CD137, 46 and demonstrated that LMP1 can induce ectopic CD137 expression on HRS cells via the PI3K-Akt-mTOR pathway. 46,54 Recently, three groups reported that CD137 deficiencies in humans lead to impaired lymphocytic responses and EBV-induced lymphoproliferation or lymphomagenesis.…”

Section: Ectopic Cd137 Expression On Hrs Cells Induced By Epstein-barmentioning

confidence: 69%

The role of trogocytosis in immune surveillance of Hodgkin lymphoma

Zeng

Schwarz

2020

OncoImmunology

Self Cite

View full text Add to dashboard Cite

Hodgkin lymphoma (HL) is a unique type of hematopoietic cancer that has few tumor cells but a massive infiltration of immune cells. Findings on how the cancerous Hodgkin and Reed-Sternberg (HRS) cells survive and evade immune surveillance have facilitated the development of novel immunotherapies for HL. Trogocytosis is a fast process of intercellular transfer of membrane patches, which can significantly affect immune responses. In this review, we summarize the current knowledge of how trogocytosis contributes to the suppression of immune responses in HL. We focus on the ectopic expression of CD137 on HRS cells, the cause of its expression, and its implication on developing novel therapies for HL. Further, we review data demonstrating that similar mechanisms apply to CD30, PD-L1 and CTLA-4.

show abstract

Section: Ectopic Cd137 Expression On Hrs Cells Induced By Epstein-barmentioning

confidence: 69%

The role of trogocytosis in immune surveillance of Hodgkin lymphoma

Zeng

Schwarz

2020

OncoImmunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Another gene upregulated in P3HR1 lymphomas is TNFRSF9 (4-1BB; CD137) (Fig 10A). CD137, which is expressed at high levels in CHL RS cells [53], and is also a known target of LMP1 [54], has been suggested to protect RS cells from T cell mediated killing by sequestering the T cell receptor activating ligand, CD137L [53]. IHC analysis confirmed that CD137 is expressed at high levels especially in the LMP1 high regions of tumors (Fig 10C).…”

Section: Fig 8 P3hr1 Infected Lymphomas Express Both Wp-restricted Amentioning

confidence: 70%

EBNA2-deleted Epstein-Barr virus (EBV) isolate, P3HR1, causes Hodgkin-like lymphomas and diffuse large B cell lymphomas with type II and Wp-restricted latency types in humanized mice

Romero-Masters

Huebner

et al. 2020

PLoS Pathog

View full text Add to dashboard Cite

EBV transforms B cells in vitro and causes human B-cell lymphomas including classical Hodgkin lymphoma (CHL), Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). The EBV latency protein, EBNA2, transcriptionally activates the promoters of all latent viral protein-coding genes expressed in type III EBV latency and is essential for EBV's ability to transform B cells in vitro. However, EBNA2 is not expressed in EBV-infected CHLs and BLs in humans. EBV-positive CHLs have type II latency and are largely driven by the EBV LMP1/LMP2A proteins, while EBV-positive BLs, which usually have type I latency are largely driven by c-Myc translocations, and only express the EBNA1 protein and viral noncoding RNAs. Approximately 15% of human BLs contain naturally occurring EBNA2-deleted viruses that support a form of viral latency known as Wp-restricted (expressing the EBNA-LP, EBNA3A/3B/3C, EBNA1 and BHRF1 proteins), but whether Wp-restricted latency and/ or EBNA2-deleted EBV can induce lymphomas in humanized mice, or in the absence of c-Myc translocations, is unknown. Here we show that a naturally occurring EBNA2-deleted EBV strain (P3HR1) isolated from a human BL induces EBV-positive B-cell lymphomas in a subset of infected cord blood-humanized (CBH) mice. Furthermore, we find that P3HR1infected lymphoma cells support two different viral latency types and phenotypes that are mutually exclusive: 1) Large (often multinucleated), CD30-positive, CD45-negative cells reminiscent of the Reed-Sternberg (RS) cells in CHL that express high levels of LMP1 but not EBNA-LP (consistent with type II viral latency); and 2) smaller monomorphic CD30-negative DLBCL-like cells that express EBNA-LP and EBNA3A but not LMP1 (consistent with Wp-restricted latency). These results reveal that EBNA2 is not absolutely required for EBV

show abstract

“…With four subgroups including nodular sclerosis (NSCHL), mixed cellularity (MCCHL), lymphocyte depletion (LDCHL), and lymphocyte-rich (LRCHL), CHL is relatively less known about genetic lesions owing to the fact that the neoplastic Hodgkinand Reed-Sternberg (HRS) cells constituting only a small proportion of the tumor tissue [293]. But the prevalence of EBV in HRS cells varies according to the histological subtype and epidemiologic factors from highest frequency in MCCHL to the lowest in NSCHL, and EBV-encoded LMP1 utilizes the PI3K/AKT/mTOR signaling axis to induce ectopic CD137 expression in HRS cells, which results in enhancing the proliferation rate of HRS cells [294,295]. Furthermore, differences related to EBV status or histological subtypes are observed for PI3K signaling in pediatric HL patients by using hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA), where MCCHL and EBV+ cases were less frequently affected by mutations in ITPKB and GNA13 genes [296].…”

Section: Description Of the Pi3k/akt Pathway In The Hemato-immune Sysmentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

View full text Add to dashboard Cite

Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

show abstract

Epstein–Barr virus-encoded LMP1 induces ectopic CD137 expression on Hodgkin and Reed–Sternberg cells via the PI3K-AKT-mTOR pathway

Cited by 25 publications

References 32 publications

The role of trogocytosis in immune surveillance of Hodgkin lymphoma

The role of trogocytosis in immune surveillance of Hodgkin lymphoma

EBNA2-deleted Epstein-Barr virus (EBV) isolate, P3HR1, causes Hodgkin-like lymphomas and diffuse large B cell lymphomas with type II and Wp-restricted latency types in humanized mice

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Contact Info

Product

Resources

About