Distinct immunopathological mechanisms of EBV‐positive and EBV‐negative posttransplant lymphoproliferative disorders

EBV-positive and EBV-negative post-transplant lymphoproliferative disorders (PTLDs) arise in different immunovirological contexts and might have distinct pathophysiologies. To examine this hypothesis, we conducted a multicentric prospective study with 56 EBV-positive and 39 EBV-negative PTLD patients of the K-VIROGREF cohort, recruited at PTLD diagnosis and before treatment (2013-2019), and compared them to PTLD-free Transplant Controls (TC, n=21). We measured absolute lymphocyte counts (n=108), analyzed NK- and T-cell phenotypes (n=49 and 94) and performed EBV-specific functional assays (n=16 and 42) by multiparamenter flow cytometry and ELISpot-IFNγ assays (n=50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival was poorer in patients with a CD4 lymphopenia (CD4+ <300 cells/mm3 , p<0.001). EBV-positive PTLD patients presented a profound NK-cell lymphopenia (median=60 cells/mm3 ) and a high proportion of NK cells expressing PD-1 (vs TC, p=0.029) and apoptosis markers (vs TC, p<0.001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune-exhaustion (p=0.013 vs TC) and poorly recognized the N-terminal portion of EBNA-3A viral protein. Altogether, this broad comparison of EBV-positive and EBV-negative PTLDs highlight distinct patterns of immunopathological mechanisms between these two diseases and provide new clues for immunotherapeutic strategies and PTLD prognosis.