| Affiliation: | 1. Sorbonne Université (Univ. Paris 06), INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Hôpital Pitié-Salpêtrière, Paris, France;2. Service d'Hématologie, Hôpital Pitié-Salpêtrière, Paris, France;3. Sorbonne Université (Univ. Paris 06), INSERM U1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Hôpital Pitié-Salpêtrière, Paris, France CNRS ERL8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France;4. Service de Néphrologie, Urologie et Transplantation Rénale, Hôpital Pitié-Salpêtrière, Paris, France;5. Service de Virologie, Hôpital Pitié-Salpêtrière, Paris, France;6. Service de Chirurgie Digestive, Hépato-Bilio-pancréatique et Transplantation Hépatique, Hôpital Pitié-Salpêtrière, Paris, France;7. Service d'Anatomopathologie, Hôpital Pitié-Salpêtrière, Paris, France |
| Abstract: | EBV-positive and EBV-negative posttransplant 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 multiparameter flow cytometry and ELISpot-IFNγ assays (n = 50). EBV-negative PTLD patients, NK cells overexpressed Tim-3; the 2-year progression-free survival (PFS) was poorer in patients with a CD4 lymphopenia (CD4+<300 cells/mm3, p < .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 = .029) and apoptosis markers (vs. TC, p < .001). EBV-specific T cells of EBV-positive PTLD patients circulated in low proportions, showed immune exhaustion (p = .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. |
