Structural Vulnerabilities in DLBCL for Enhanced Treatment Strategies

Abstract

Abstract Diffuse large B-cell lymphoma (DLBCL) is a typically immune-suppressed lymphoma subtype with poor response to immune checkpoint blockade and chimeric antigen receptor T-cell therapy. Recent data demonstrated an association between an activated, myofibroblast-like tumor stroma with improved outcome. On the basis of these findings, Apollonio and colleagues explored the phenotypic, transcriptional, and functional state of fibroblastic reticular cells (FRC) in human and murine DLBCL. This study reveals that DLBCL cells trigger the activation and remodeling of FRCs, leading to a chronic inflammatory state that supports malignant B-cell survival. Transcriptional reprogramming of the FRCs may inhibit CD8+ T-cell migration and function through changes in homing chemokines, adhesion molecules, and antigen presentation machinery, which together limit the anti-DLBCL immune response. High-dimensional imaging mass cytometry revealed heterogeneous CD8+ T-cell and FRC neighborhoods that associated with different clinical outcomes and ex vivo modeling of the microenvironment indicated an opportunity to target the FRC network for improved T-cell motility, infiltration, and effector function. This research broadens our understanding of the complex interactions between the lymph node microarchitecture and antitumor immune surveillance, defines structural vulnerabilities in DLBCL, and thereby offers opportunities for combined therapeutic approaches.