Systemic Inflammation and Tumour-Infiltrating T-Cell Receptor Repertoire Diversity Are Predictive of Clinical Outcome in High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements

SIMPLE SUMMARY: The current version of the World-Health-Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues acknowledges the provisional entity of high-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) which is associated with dire prognosis compared to triple-negative diffuse-large-B-cell-lymphoma (tnDLBCL). There is growing evidence for the essential prognostic role of the tumor-microenvironment (TME) and especially the extent of tumor-infiltration by the adaptive immune-system through tumor-infiltrating-lymphocytes (TIL) across a variety of cancers. More precisely, the clonal-architecture of the tumor-infiltrating T-cell-receptor (TCR)-repertoire has recently emerged as a key determinant of risk-stratification in patients with hematological malignancies. Moreover, inflammation-based prognostic-scores, such as the Glasgow-prognostic-score (GPS) were shown to reflect the TME. We therefore performed a large scale next-generation-sequencing (NGS) and clinicopathological study of the TCR-β-chain-repertoire in HGBL-DH/TH revealing several entity-exclusive clonotypes distinct from tnDLBCL, suggestive of tumor-neoantigen-selection and correlate our findings with the GPS in context of clinical outcome in HGBL-DH/TH. ABSTRACT: High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 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: p = 0.0273; HR: 2.839; CI: 1.124–7.169; maximum productive frequency: p = 0.0307; HR: 2.167; CI: 1.074–4.370) but not PFS (productive clonality: p = 0.4459; maximum productive frequency: p = 0.5567) in HGBL-DH/TH patients, while GPS was a significant predictor of both OS and PFS (OS: p < 0.0001; PFS: p = 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: p = 0.038; R-IPI: p = 0.006) and PFS (GPS: p = 0.029; R-IPI: p = 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.