Characterization and Clinical Impact of the Tumor Microenvironment of Post-Transplant Large B-Cell Lymphoma

Abstract

Post-transplant lymphoproliferative disorders (PTLDs) arise after solid organ or allogeneic hematopoietic stem cell transplantation. They are characterized by abnormal proliferation of lymphoid cells associated with immunosuppression and comprise three histological categories (non-destructive, polymorphic, monomorphic) entailing a heterogeneous clinical behavior. The majority of monomorphic PTLDs fulfill the criteria of aggressive large B-cell lymphomas and are often associated with Epstein-Barr virus (EBV) positivity. The composition and function of the tumor microenvironment (TME) has a major impact on lymphoma development and survival, but to date, only few studies investigating the TME in PTLD have been reported. We used digital gene expression profiling and in silico immunophenotyping to characterize the TME of 75 post-transplant monomorphic aggressive B-cell lymphomas from three Nordic countries and correlated the findings with patient demographics (Table 1) and survival. Unsupervised clustering demonstrated a high degree of heterogeneity and variation in the immune response profile among the PTLDs. EBV+ PTLDs clustered closely together and were enriched for type I interferon signaling and antiviral response genes. In addition, a signature for cytotoxicity associated with EBV-positivity and better overall survival (OS; HR 0.61, 95%CI 0.40-0.92, P=0.019). In silico immunophenotyping utilizing CIBERSORTx suggested that the PTLDs can be divided into two subgroups with distinct immune cell compositions (Figure 1). The patients in the inflamed subgroup with high proportions of T cells and NK cells, as well as high T cell/macrophage ratio, had significantly better OS and PFS compared to the patients in the non-inflamed subgroup (median OS >200.0 vs. 15.2 months, P=0.006; median PFS 89.0 vs. 14.4 months, P=0.049). In multivariable analysis with the EBV-status, International Prognostic Index (IPI) and rituximab-containing treatment, the inflamed TME remained as an independent predictor for favorable OS and PFS. The inflamed subgroup was associated with EBV-positivity (P=0.008) and earlier onset of the disease (P=0.004). We also compared the TME composition between post-transplant and de novo diffuse large B-cell lymphomas (DLBCLs, n=82) and discovered that the PTLD TME was enriched in dendritic cells, NK cells, and activated mast cells, whereas the proportion of T cells, memory B cells and resting mast cells was lower compared to the de novo DLBCL. In conclusion, we provide a comprehensive phenotypic characterization of PTLD, highlighting the importance of TME biology, and in particular T cell infiltration, in the clinical behavior and prognosis of PTLD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal