Simple Summary Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoid neoplasm and includes morphologically and molecularly heterogeneous disease subtypes. Genetic aberrations of tumor cells are strongly related to the signature of the tumor microenvironment. In this review, we summarize common genetic aberrations associated with immune escape, immune cell subs involved in DLBCL pathogenesis, and distinct microenvironmental signatures identified using next-generation sequencing and single-cell technologies. We also discuss the pathogenic role of immunosenescence in Epstein-Barr virus-positive DLBCL. Moreover, as DLBCL exhibits unique pathogenesis in immune-privileged sites, we also present a hypothetical model of DLBCL development in immune-privileged sites. Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and is the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival and proliferation activity, others depend on interactions with non-malignant cells for their survival and proliferation. Recent next-generation sequencing studies have linked these interactions with the molecular classification of DLBCL. For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex. Single-cell technologies have also provided detailed information about cell–cell interactions and the cell composition of the microenvironment of DLBCL. Aging-related immunological deterioration, i.e., immunosenescence, also plays an important role in DLBCL pathogenesis, especially in Epstein-Barr virus-positive DLBCL. Moreover, DLBCL in “immune-privileged sites”—where multiple immune-modulating mechanisms exist—shows unique biological features, including frequent down-regulation of immune recognition molecules and an immune-tolerogenic tumor microenvironment. These advances in understanding the immunology of DLBCL may contribute to the development of novel therapies targeting immune systems.

/pdf/the-immunology-of-dlbcl-2c7mqvr2.pdf

The Immunology of DLBCL

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma curable even in advanced stages. DLBCL involving the central nervous system (CNS) is more difficult to cure and fewer treatment options exist. Primary CNS lymphoma (PCNSL) refers to aggressive lymphomas confined to the CNS, and are almost always DLBCL. Standard approaches for PCNSL use high-dose methotrexate based combinations as induction therapy and younger patients often receive dose-intensive consolidation. However, dose-intensive therapies are not suitable for all patients, and older patients have fewer effective treatment options. Patients with relapsed or chemotherapy-refractory disease have a grave prognosis. Secondary CNS lymphoma (SCNSL) describes aggressive lymphomas involving the CNS at initial presentation or relapses within the CNS after treatment for systemic DLBCL. Isolated CNS relapse is often managed as PCNSL, but patients with synchronous involvement of DLBCL in both the periphery and the CNS pose a unique clinical challenge. Insights into the molecular circuitry of DLBCL have identified distinct genetic subtypes including cases with a predilection for CNS invasion. PCNSL and subsets of SCNSL are characterised by chronically activated B-cell receptor and NFKB signalling along with genetic evidence of immune evasion which may be exploited therapeutically. Improved mechanistic understanding of targetable pathways underpinning CNS lymphomas has led to numerous clinical trials testing targeted agent combinations and immunotherapy approaches with promising early results. Biologically rational strategies may further improve the cure rate of CNS lymphomas either by overcoming intrinsic or acquired treatment resistance and/or by being broadly applicable to patients of all ages.

pdf/diffuse-large-b-cell-lymphoma-involving-the-central-nervous-a383h6v9hy.pdf

Diffuse large B-cell lymphoma involving the central nervous system: biologic rationale for targeted therapy.

Approximately 30% of lymphomas occur outside the lymph nodes, spleen, or bone marrow, and the incidence of extranodal lymphoma has been rising in the past decade. While traditional chemotherapy and radiation therapy can improve survival outcomes for certain patients, the prognosis for extranodal lymphoma patients remains unsatisfactory. Extranodal lymphomas in different anatomical sites often have distinct cellular origins, pathogenic mechanisms, and clinical manifestations, significantly influencing their diagnosis and treatment. Therefore, it is necessary to provide a comprehensive summary of the pathogenesis, diagnosis, and treatment progress of extranodal lymphoma overall and specifically for different anatomical sites. This review summarizes the current progress in the common key signaling pathways in the development of extranodal lymphomas and intervention therapy. Furthermore, it provides insights into the pathogenesis, diagnosis, and treatment strategies of common extranodal lymphomas, including gastric mucosa-associated lymphoid tissue (MALT) lymphoma, mycosis fungoides (MF), natural killer/T-cell lymphoma (nasal type, NKTCL-NT), and primary central nervous system lymphoma (PCNSL). Additionally, as PCNSL is one of the extranodal lymphomas with the worst prognosis, this review specifically summarizes prognostic indicators and discusses the challenges and opportunities related to its clinical applications. The aim of this review is to assist clinical physicians and researchers in understanding the current status of extranodal lymphomas, enabling them to make informed clinical decisions that contribute to improving patient prognosis. 

Extranodal lymphoma: pathogenesis, diagnosis and treatment

Chimeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r) diffuse large B cell lymphoma (DLBCL) patients treated with tisagenlecleucel. This finding leads to the development of the CAR/CCR (chimeric checkpoint receptor) design, which consists of a CD19-specific first-generation CAR co-expressed with a recombinant CTLA-4-linked receptor with a 4-1BB co-stimulatory domain. CAR/CCR T cells demonstrate superior efficacy in xenograft mouse models compared with CAR T cells, superior long-term activity, and superior selectivity in in vitro assays with non-malignant CD19+ cells. In addition, immunocompetent mice show an intact CD80−CD19+ B cell population after CAR/CCR T cell treatment. The results reveal the CAR/CCR design as a promising strategy for further translational study. 

An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL.

Diffuse large B cell lymphoma (DLBCL) is a genetically highly heterogeneous disease. Yet, to date, the vast majority of patients receive standardized frontline chemo-immune-therapy consisting of an anthracycline backbone. Using these regimens, approximately 65% of patients can be cured, whereas the remaining 35% of patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. To systematically tackle this high medical need, it is important to design, generate and deploy suitable in vivo model systems that capture disease biology, heterogeneity and drug response. Recently published, large comprehensive genomic characterization studies, which defined molecular sub-groups of DLBCL, provide an ideal framework for the generation of autochthonous mouse models, as well as an ideal benchmark for cell line-derived or patient-derived mouse models of DLBCL. Here we discuss the current state of the art in the field of mouse modelling of human DLBCL, with a particular focus on disease biology and genetically defined molecular vulnerabilities, as well as potential targeting strategies.

Mouse models of diffuse large B cell lymphoma

Novel mouse models of Myd88-driven DLBCL serve as preclinical platforms to evaluate combined BTK/BCL2 inhibition and immune-therapeutic approaches.

https://doi.org/10.1158/2643-3230.bcd-22-0007

Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

A third of diffuse large B-cell lymphoma (DLBCL) patients present with extranodal dissemination, associated with inferior clinical outcome. MYD88L265P is a hallmark extranodal DLBCL mutation that supports lymphoma proliferation. Yet, extranodal lymphomagenesis and the role of MYD88L265P in transformation remain mostly unknown. Here, we show that B-cells expressing Myd88L252P (MYD88L265P murine equivalent) activate, proliferate, and differentiate, with minimal T-cell co-stimulation. Additionally, Myd88L252P skewed B-cells towards the memory fate. Unexpectedly, the transcriptional and phenotypic profiles of B-cells expressing Myd88L252P, or other extranodal lymphoma founder mutations, resembled those of CD11c+T-BET+ aged/autoimmune memory B-cells (AiBC). AiBC-like cells progressively accumulated in animals prone to develop lymphomas, and ablation of T-BET, the AiBC master regulator, stripped mouse and human mutant B-cells of their competitive fitness. By identifying a phenotypically-defined prospective lymphoma precursor population and its dependencies, our findings pave the way for the early detection of premalignant states and targeted prophylactic interventions in high-risk patients.

An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas.

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Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas.