The implication of Epstein-Barr virus latent membrane protein 1 on the composition and prognostic significance of the tumor microenvironment of classical Hodgkin lymphoma

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Abstract Purpose Epstein-Barr virus (EBV) is crucial for the pathogenesis of classical Hodgkin lymphoma (CHL). In this study, we evaluated whether the EBV could predict the clinical behavior of CHL and impact the tumor microenvironment(TME) signatures. Methods We conducted immunohistochemical analyses for the expression of EBV-latent membrane protein 1 (LMP1) and markers reflecting immune cells, including CD3, CD4, CD8, FOXP3, CD20, and CD68 in 102 CHL samples and calculated the ratios between cell subsets for each specimen. Results EBV-LMP1 positivity was detected in 35 (34%) cases and remained an independent poor prognostic factor for overall survival (OS) (p = 0.022). In addition, the CD8/FOXP3+ ratio was significantly increased in LMP1+ than in LMP1- tumors (p = 0.027). Using Cox modeling, a high CD8/CD68+ ratio was associated with shorter OS in LMP1+ tumors compared to a low CD8/CD68+ ratio (p = 0.039); however, neither CD8+ nor CD68+ separately was correlated to the CHL survival. Moreover, the Kaplan-Meier method showed an association of a high CD8/CD68+ ratio with inferior OS in LMP1+ tumors (p = 0.013). In multivariate analysis, a high CD8/CD68+ ratio and B-symptoms tended to be independent prognostic factors for OS (HR = 9.80 (0.56-171.5), p = 0.11; HR = 10.28 (1.00-106.0), p= 0.05; respectively). Conclusion EBV-LMP1+ is an independent unfavorable prognostic factor for CHL, modulating the TME towards a cytotoxic profile. Besides, CD8/CD68+ ratio could be a potential factor acccruately predicting the clinical outcomes of LMP1+ CHL patients, providing more prgnostic information than each cell seperately.

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