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

Wright, K.

Blood Advances

2023

Context:

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified, stands as the most prevalent aggressive non-Hodgkin lymphoma, characterized by its biological heterogeneity. Despite advancements in immunotherapies, the intricate organization of the DLBCL tumor-immune microenvironment (TIME) remains elusive.

Methodology:

In this study, the researchers meticulously examined the intact TIME of 51 de novo DLBCL cases through triplicate sampling. This comprehensive analysis involved characterizing 337,995 tumor and immune cells using a sophisticated 27-plex antibody panel. This panel enabled them to capture cell lineage, architectural, and functional markers. By spatially assigning individual cells, identifying local cell neighborhoods, and establishing their topographical organization in situ, they discovered that the organization of local tumor and immune cells can be modeled into six composite cell neighborhood types (CNTs).

Results:

Their findings revealed that differential CNT representation categorizes cases into three distinct aggregate TIME categories: immune-deficient, dendritic cell–enriched (DC-enriched), and macrophage-enriched (Mac-enriched).

Immune-Deficient TIME: These cases are characterized by tumor cell–rich CNTs with minimal infiltrating immune cells, predominantly located near CD31+ vessels, indicating limited immune activity.
DC-Enriched TIME: These cases feature tumor cell–poor/immune cell–rich CNTs with a high presence of CD11c+ dendritic cells and antigen-experienced T cells, also enriched near CD31+ vessels, suggesting heightened immune activity.
Mac-Enriched TIME: These cases are marked by tumor cell–poor/immune cell–rich CNTs with a significant number of CD163+ macrophages and CD8 T cells dispersed throughout the microenvironment. This is accompanied by increased IDO-1 and LAG-3 expression and decreased HLA-DR expression, indicative of immune evasion mechanisms.

Implications:

Their research underscores that the heterogeneous cellular components of DLBCL are not randomly distributed but are organized into CNTs that define aggregate TIMEs with distinct cellular, spatial, and functional characteristics. This structured organization of DLBCL cell neighborhoods into immune-deficient, DC-enriched, and macrophage-enriched microenvironments provides crucial insights into the tumor-immune dynamics and could inform future therapeutic strategies.

Model: Human

Indication: Oncology

Assay: Proteomics, DNA

Diffuse large B-cell lymphoma (DLBCL) not otherwise specified is the most common aggressive non-Hodgkin lymphoma and a biologically heterogeneous disease. Despite the development of effective immunotherapies, the organization of the DLBCL tumor-immune microenvironment (TIME) remains poorly understood.We interrogated the intact TIME of 51 de novo DLBCLs with triplicate sampling to characterize 337 995 tumor and immune cells using a 27-plex antibody panel that captured cell lineage, architectural, and functional markers. We spatially assigned individual cells, identified local cell neighborhoods, and established their topographical organization in situ. We found that the organization of local tumor and immune cells can be modeled by 6 composite cell neighborhood types (CNTs). Differential CNT representation divided cases into 3 aggregate TIME categories: immune-deficient, dendritic cell–enriched (DC-enriched), and macrophage-enriched (Mac-enriched). Cases with immune-deficient TIMEs have tumor cell–rich CNTs, in which the few infiltrating immune cells are enriched near CD31+ vessels, in keeping with limited immune activity. Cases with DC-enriched TIMEs selectively include tumor cell–poor/immune cell–rich CNTs with high numbers of CD11c+ DCs and antigen-experienced T cells also enriched near CD31+ vessels, in keeping with increased immune activity. Cases with Mac-enriched TIMEs selectively include tumor cell–poor/immune cell–rich CNTs with high numbers of CD163+ macrophages and CD8 T cells throughout the microenvironment, accompanied by increased IDO-1 and LAG-3 and decreased HLA-DR expression and genetic signatures in keeping with immune evasion. Our findings reveal that the heterogenous cellular components of DLBCL are not randomly distributed but organized into CNTs that define aggregate TIMEs with distinct cellular, spatial, and functional features.