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

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.

Angioimmunoblastic T-cell lymphoma with predominant CD8+ tumor-infiltrating T-cells is a distinct immune pattern with an immunosuppressive microenvironment

“…Accordingly, our findings in the TRB repertoire of the CD8-predominant AITL TME may be interpreted by TME immunosuppression. Additionally, in keeping with knowledge from other tumors ( 13 , 32 ), the narrowed TR and IGH repertoires in the TME of CD8-predominant AITL may indicate downregulated anti-tumor immunity via inadequate immunosurveillance of tumor T-cell neoantigens.…”

“…TIL subsets and proportions directly reflected TME immune function and have been shown to be predictive of various malignancies ( 17 – 19 ). TR and IGH repertoires of TME dictate TIL-T and TIL-B variety and represent the ability to identify tumor antigens and combat tumor immunoevasion ( 13 , 14 ). Furthermore, gene expression profiling may reveal immunological activity by examining the regulation of related pathways.…”

“…Both shared and differential clones with a specific complementarity determining region 3 (CDR3) sequence between the two AITL groups were identified. These analyses were performed on R using the "LymphoSeq" and "tcR" packages (12)(13)(14)(15).…”

Read the clonotype: Next-generation sequencing-based lymphocyte clonality analysis and perspectives for application in pathology

“…In melanoma, breast and colon cancer, expanded Tcell clones are associated with response to immunotherapy treatment (77)(78)(79). In BCL, a restricted TR repertoire is found to be associated with poor outcome in DLBCL treated without immune-checkpoint inhibition (80) and in high grade B-cell lymphomas (81). Obviously, more studies are needed for different lymphoma types and treatments to understand the full potential of TR repertoire analysis in BCL.…”

The Glasgow Prognostic Score Predicts Survival Outcomes in Neuroendocrine Neoplasms of the Gastro–Entero–Pancreatic (GEP-NEN) System

“…The cut-off values of Ki-67 for optimal risk stratification are discussed conversely [ 29 , 30 , 31 ]. Among a large spectrum of solid tumors and hematological malignancies, it has been shown that the Glasgow Prognostic Score (GPS) reflects a representative and handy tool to identify cancer patients at risk for both early progression and all-cause mortality [ 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. GPS examines two essential mechanisms of tumor growth, progression and aggressiveness.…”