Diffuse large B-cell lymphomas have spatially defined, tumor immune microenvironments revealed by high-parameter...

Area of Science:

• Oncology
• Immunology
• Computational Biology

Background:

• Diffuse large B-cell lymphoma (DLBCL) is an aggressive, heterogeneous non-Hodgkin lymphoma.
• Understanding the tumor-immune microenvironment (TIME) is crucial for effective immunotherapy in DLBCL.
• The spatial organization of cells within the DLBCL TIME is poorly understood.

Purpose of the Study:

• To characterize the intact tumor-immune microenvironment (TIME) in de novo DLBCL.
• To identify distinct cellular neighborhoods and their spatial organization within DLBCL.
• To define aggregate TIME categories based on composite cell neighborhood types (CNTs).

Main Methods:

• Interrogation of the TIME in 51 de novo DLBCLs using triplicate sampling.
• Characterization of 337,995 tumor and immune cells with a 27-plex antibody panel.
• Spatial assignment of individual cells, identification of local cell neighborhoods, and topographical organization analysis.

Main Results:

• Six composite cell neighborhood types (CNTs) were identified, modeling local tumor and immune cell organization.
• Differential CNT representation classified DLBCL cases into three aggregate TIME categories: immune-deficient, dendritic cell-enriched (DC-enriched), and macrophage-enriched (Mac-enriched).
• Each TIME category exhibited distinct cellular compositions, spatial distributions, and functional features, including immune activity and evasion markers.

Conclusions:

• DLBCL cellular components are not randomly distributed but organized into spatially defined CNTs.
• These CNTs define aggregate TIMEs with distinct cellular, spatial, and functional characteristics.
• The identified TIME categories provide insights into DLBCL heterogeneity and potential therapeutic strategies.