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Immuniteit, het Epstein-Barr virus en de micro-omgeving in lymfomen: karakterisatie van lymfoïde weefsels en rationale voor nieuwe therapeutische opportuniteiten

Book - Dissertation

For this PhD thesis we studied a set of rare B-cell lymphoproliferative disorders (LPDs): immunomodulation related lymphoproliferative disorders (IARLPD) and primary central nervous system lymphoma (PCNSL) using both classical and novel pathology techniques. We are currently expanding upon this research with an ongoing project studying EBV+ diffuse large B-cell lymphoma (EBV+ DLBCL). All with the aim of aiding the correct implementation of novel immunotherapy strategies for patients suffering from these aggressive diseases. 1. Immunomodulation related lymphoproliferative disorders (IARLPD) The development of LPDs is a known complication in patients with chronic suppression or modulation of the immune system. Although an increasing incidence of IARLPD is observed, the characterization of this group is still limited to small series. As new immunomodulatory agents continue to become available and the number of patients receiving immunomodulatory/suppressive therapy increases, more awareness for this entity is warranted. We described the clinicopathological characteristics of a large single-center series of 72 immunomodulatory/suppressive agent-related lymphoproliferative disorder cases. An ongoing discussion is how similar IARLPDs are to the already better characterized PTLDs. When comparing this case series with a published series of 140 post-transplant lymphoproliferative disorder cases from our center we observed a similar histopathological spectrum from non-destructive (n=12), to polymorphic (n=8), Hodgkin (n=6) and monomorphic (n=44) lesions as described in PTLD. The IARLPDs were however less often associated with the Epstein-Barr virus (EBV) (31% vs 66%; p=1,829e-05) and the lymphoproliferative disorders incidence in the first year after therapy initiation was lower (18% vs 41%; p= 0,04151). The common histological spectrum points towards shared underlying lymphomagenesis mechanisms related to immune function impairment and differences in both EBV prevalence and difference in time of LPD development are likely related to the severity of the immunosuppression/immunomodulation. We also observed differences in time to LPD development with a shorter time for all the immunomodulatory drug-related cases combined (immunomodulatory and immunomodulatory + immunosuppressive = immunomodulatory-all) vs immunosuppressive (p=0,0031). The large variation in therapeutic regiments leading up to LPD development complicate the drawing of major conclusions, nevertheless the association of lymphomagenesis with (iatrogenic) alterations in immune function implies that aiding the immune system through immunotherapy has potential benefits. Correct classification of IARLPD is essential to allow proper validation of novel therapeutics in clinical trials and more in depth characterization of all immune cells present in the tumor microenvironment (TME) is warranted and underway in ongoing research. 2. Primary central nervous system lymphoma (PCNSL) Primary central nervous system lymphoma is defined by the 2017 revised WHO as an extranodal, malignant non-Hodgkin lymphoma that arises in the central nervous system (CNS) in the absence of prior or concurrent systemic lymphoma3. The majority of cases are classified as diffuse large B-cell lymphoma (DLBCL). Very little is known about the TME of lymphoma in the CNS and important to note is that the CNS is in normal situations an 'immune privileged' site with minimal immune surveillance. To investigate the potential of immunotherapies such as immune-checkpoint therapy we retrospectively studied the tumor microenvironment (TME) using multiple techniques including high-plex immunohistochemistry in 22 PCNSL and compared to 7 secondary CNS lymphomas (SCNSL) and 7 "other" CNSL lymphomas with presence of the Epstein-Barr virus and/or compromised immunity. The TME in PCNSL was predominantly composed of CD8+ cytotoxic T-cells and CD163+ phagocytes. Despite molecular differences between PCNSL and SCNSL, the cellular composition as well as the functional spectrum of cytotoxic T-cells were similar. But cytotoxic T-cell activation was significantly influenced by pre-biopsy corticosteroids intake, tumor expression of PD-L1 and the presence of EBV. The presence of low numbers of CD8+ T-cells and geographic-type necrosis each predicted inferior outcome in PCNSL (p=0,0014 and p=0,024 respectively). Both M1-like (CD68+CD163low) and M2-like (CD68+CD163high) phagocytes were identified, and an increased ratio of M1-like/M2-like phagocytes was associated to a better survival (ratio: 0,85; p=0,0094). PD-L1 was expressed in lymphoma cells in 28% of cases, while PD1 was expressed in only 0,4% of all CD8+ T-cells. TIM-3, a marker for T-cell exhaustion, was significantly more expressed in CD8posPD-1pos T-cells compared to CD8posPD-1neg T-cells (area under the ROC curve of 0,046 AUC), and a similar increased expression was observed in M2-like pro-tumoral phagocytes. The clinical impact of TME composition supports the use of immune checkpoint therapies in PCNSL. Based on observed differences in immune checkpoint expression, combinations that boost cytotoxic T-cell activation prior to the administration of PD-L1 inhibition (e.g. association with anti-TIM-3 immunotherapy) could be of interest. The digital pathology and high-plex staining methods employed in this study provided additional insight and are valid techniques for further investigation of the TME in lymphoma.
Publication year:2020
Accessibility:Closed