The tumour microenvironment is immuno‐tolerogenic and a principal determinant of patient outcome in EBV‐positive diffuse large B‐cell lymphoma

Abstract

ObjectiveEpstein‐Barr virus‐positive diffuse large B‐cell lymphoma (EBV‐pos DLBCL) is a recently identified entity. Data regarding outcome to frontline immuno‐chemotherapy are conflicting. Although the prognostic impact of the tumour microenvironment (TME) in EBV‐neg DLBCL is well‐established, it remains untested whether the TME influences survival in EBV‐pos DLBCL. There are no data with new digital gene expression technologies that simultaneously interrogate the virus, B cells and the tumour microenvironment (TME).MethodsWe used the NanoString™ platform in a population‐based cohort of 433 patients to establish if the technology could detect EBV in the tumour biopsies and to investigate the influence that EBV has on the complex tumour microenvironment of DLBCL.ResultsIncidence of EBV‐pos DLBCL was 6.9% with 5‐year survival of 65% vs 82% in EBV‐neg DLBCL (P = 0.018). EBV‐pos tissues had similar expression of T‐cell genes compared to EBV‐neg DLBCL but higher levels of the antigen‐presenting molecule B2M. This was countered by elevated PD‐L1, PD‐L2, LAG3 and TIM3 immune checkpoints and a higher CD163/CD68 “M2” macrophage score.ConclusionIn EBV‐pos DLBCL, the TME is immuno‐tolerogenic and may explain the poor outcomes seen in this subtype of DLBCL.

EBV microRNA-BHRF1-2-5p targets the 3′UTR of immune checkpoint ligands PD-L1 and PD-L2

“…It is postulated that EBV 1 DLBCL has a tolerogenic tumor microenvironment that promotes immune escape, 27,56 much as iatrogenic immunosuppression does in EBV 1 PTLD. 57,58 In keeping with this, although substantially higher clonal T-cell responses are observed in EBV 1 DLBCL vs DLBCL NOS, 59 EBV 1 DLBCL biopsies are associated with high levels of PD-L1 and PD-L2.…”

“…20 NanoString for COO using Lymph2Cx and EBER in situ hybridization (ISH) were performed as previously described. 27,28 Microarray data sets of B-cell differentiation stages were used for comparison with our qRT-PCR data (supplemental Methods, available on the Blood Web site).…”

Gene expression profiling of gray zone lymphoma

“…Others previously reported a specific TME for EBV-DLBCL vs DLBCL, with an elevated M2 macrophage score as assessed by using NanoString methods. 39 These polymorphic-EBV-L patients might benefit from improved therapeutic approaches, such as emerging EBV-specific cellular therapy options. 40,41 In conclusion, we provide a comprehensive phenotypic characterization of GZL, highlighting the importance of TME biology and macrophage infiltration in particular.…”

Epstein-Barr virus and its prognostic value in a cohort of Peruvian women with cervical cancer

“…In this study, we hypothesized that the presence of EBV infection in cervical tissue could have produced a negative prognostic effect in CC, this based on previous findings reported in patients with aggressive B-cell lymphomas where EBV infection was correlated with worse survival rates (10,18), and also based on previous reports showing that EBV can enhance and accelerate HPV integration to promote tumor progression (32). However, in our cohort of Peruvian women with cervical cancer, EBV infection was associated with an improved OS compared to EBV-negative individuals.…”

“…Different mechanisms have been postulated in regards to the synergic effect HPV and EBV co-infection exerts on tumor development and progression (17). Furthermore, the impact of EBV infection on survival in cancer patients is well documented with poor prognosis noticed in patients with lymphoma (10,18), as opposed to patients with certain carcinomas such as gastric and nasopharyngeal carcinomas (11,12).…”