Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies

Abstract

The Epstein–Barr virus (EBV) can cause different types of cancer in human beings when the virus infects different cell types with various latent patterns. EBV shapes a distinct and immunosuppressive tumor microenvironment (TME) to its benefit by influencing and interacting with different components in the TME. Different EBV-associated malignancies adopt similar but slightly specific immunosuppressive mechanisms by encoding different EBV products to escape both innate and adaptive immune responses. Strategies reversing the immunosuppressive TME of EBV-associated malignancies have been under evaluation in clinical practice. As the interactions among EBV, tumor cells, and TME are intricate, in this review, we mainly discuss the epidemiology of EBV, the life cycle of EBV, the cellular and molecular composition of TME, and a landscape of different EBV-associated malignancies and immunotherapy by targeting the TME.

The prognostic value of Epstein−Barr virus infection in Hodgkin lymphoma: A systematic review and meta-analysis

“…As LMP1 has antigenicity, LMP1 could activate cytotoxic T lymphocytes (CTLs) more effectively, resulting in a stronger antitumor immune response ( 64 ), which may in turn limit disease progression. However, cytotoxic T-cell responses have been observed to decline with age ( 65 , 66 ), and another possibility is immunosenescence, in which the impaired immune system is unable to respond effectively to viral infection, allowing EBV reactivation and oncogenic transformation ( 67 ). In summary, the younger group has a beneficial EBV-specific immune response to the tumor cell population, whereas in older patients, this response may be less effective or other negative prognostic factors may outweigh any beneficial effect EBV may have.…”

“…At present, the mechanism by which EBV acts on HL is still unclear ( 69 ). In EBV-positive HL, viral infection of malignant tumor cells is characterized by the consistent expression of three EBV-associated viral proteins (EBNA1, LMP1, and LMP2A) and two noncoding RNAs (EBERs and BARTs) ( 67 ), which are believed to play important roles in tumorigenesis, including the regulation of proliferation, metastasis, immune escape, and apoptosis ( 70 , 71 ). EBNA1 enhanced the activity of the AP‐1 transcription factor, triggering the induction of VEGF and IL‐8 ( 72 ); meanwhile, this protein can inhibit the antigenic peptide bound to major histocompatibility complex 1 (MHC-1) to evade recognition by CTL ( 73 ).…”

EBV-associated diseases: Current therapeutics and emerging technologies

“…The EBV virion has a diameter of 150–170 nm, consists of a linear, ~172 kbp double stranded DNA that codes for more than 85 protein coding genes ( 65 , 66 ). However, the exact function of 30-40% of these genes remains unknown ( 67 ). The EBV genome also has several tandem repeat regions that serve various functions ( 20 , 68 ).…”

“…The WHO classification describes three clinical variants of BL: endemic (eBL), sporadic (sBL), and immunodeficiency-related (usually HIV-related) ( 164 ). While around 95% of eBL are EBV + , only 15% of sBL and 40% of immunodeficiency-related BLs are associated with EBV ( 67 ). Despite primarily having the type I latency programs, some other EBV genes (e.g., EBNA2) are sporadically detected ( 165 ).…”

“…Together, these changes facilitate tumor growth by several mechanisms including promoting immune evasion. Extensive research has been done to understand the TME of both EBV – and EBV + malignancies ( 67 ). Studies on the TME are limited for certain EBV + malignancies due to low incidence rates (e.g.…”