Epstein-Barr Infection, Hodgkin's Lymphoma, and the Immune System: Insights into the Molecular Mechanisms Facilitating Immune Evasion.

Epstein-Barr virus (EBV) constitutes a very common pathogen and a well-characterized carcinogen. EBV has the ability to establish a chronic latent infection, during which only a subset of the viral genes is expressed. EBV is implicated in multiple malignancies, including Hodgkin's lymphoma (HL). HL mainly affects adolescents and young adults and has an overall favorable prognosis. However, relapsed or refractory disease still poses a therapeutic challenge. EBV does not only induce malignant transformation but also hinders the detection and clearance of the neoplastic cells by the immune system. The proteins and non-coding RNAs expressed in latency IIa, which is associated with HL, employ a variety of mechanisms to target different steps of innate and adaptive immunity, to take advantage of the immunosuppressant effect of immune checkpoints, and to shape the microenvironment to support the survival and proliferation of malignant cells. They suppress the expression or promote the degradation of pattern-recognition receptors, interfere with type I interferon and proinflammatory cytokine mediated signaling, and hinder the effector function of natural killer cells. The processing and presentation of peptides to CD4 and CD8 T cells are also hampered. EBV induces the expression of immune checkpoints, the secretion of immunosuppressive cytokines, and the efflux of regulatory T cells in the tumor microenvironment. The current review provides a comprehensive overview of the molecular mechanisms underlying this complex interplay between EBV and the immune system in HL with focus on clinical data from the pediatric population, which is the key for developing novel, effective therapeutic interventions.