Systemic Inflammation and Tumour-Infiltrating T-Cell Receptor Repertoire Diversity Are Predictive of Clinical Outcome in High-Grade B-Cell Lymphoma with and and/or Rearrangements.

High-grade B-cell lymphoma, with and and/or rearrangements (double/triple-hit high grade B-cell lymphoma, HGBL-DH/TH) constitutes a provisional entity among B-cell malignancies with an aggressive behavior and dire prognosis. While evidence for the essential prognostic role of the composition of the tumor-microenvironment (TME) in hematologic malignancies is growing, its prognostic impact in HGBL-DH/TH remains unknown. In this study, we outline the adaptive immune response in a cohort of 47 HGBL-DH/TH and 27 triple-negative diffuse large B-cell lymphoma (tnDLBCL) patients in a large-scale, next-generation sequencing (NGS) investigation of the T-cell receptor (TCR) β-chain repertoire and supplement our findings with data on the Glasgow-Prognostic Score (GPS) at diagnosis, as a score-derived measure of systemic inflammation. We supplement these studies with an immunophenotypic investigation of the TME. Our findings demonstrate that the clonal architecture of the TCR repertoire of HGBL-DH/TH differs significantly from tnDLBCL. Moreover, several entity-exclusive clonotypes, suggestive of tumor-neoantigen selection are identified. Additionally, both productive clonality and percentage of maximum frequency clone as measures of TCR repertoire diversity and tumor-directed activity of the adaptive immune system had significant impact on overall survival (OS; productive clonality: = 0.0273; HR: 2.839; CI: 1.124-7.169; maximum productive frequency: = 0.0307; HR: 2.167; CI: 1.074-4.370) but not PFS (productive clonality: = 0.4459; maximum productive frequency: = 0.5567) in HGBL-DH/TH patients, while GPS was a significant predictor of both OS and PFS (OS: < 0.0001; PFS: = 0.0002). Subsequent multivariate analysis revealed GPS and the revised international prognostic index (R-IPI) to be the only prognosticators holding significant impact for OS (GPS: = 0.038; R-IPI: = 0.006) and PFS (GPS: = 0.029; R-IPI: = 0.006) in HGBL-DH/TH. Through the identification of expanded, recurrent and entity-exclusive TCR-clonotypes we provide indications for a distinct subset of tumor-neoantigenic elements exclusively shared among HGBL-DH/TH. Further, we demonstrate an adverse prognostic role for both systemic inflammation and uniform adaptive immune response.