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Large B cell lymphoma microenvironment archetype profiles
Xubin Li1, Kartik Singhal2, Qing Deng3
1Department of Lymphoma and Myeloma, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA; Lymphoid Malignancies Program, UT MD Anderson Cancer Center, Houston, TX, USA.
Insights
This study reveals distinct lymphoma microenvironment archetypes (LymphoMAPs) in large B cell lymphomas (LBCL). These archetypes, defined by cell compositions, impact T cell interactions and predict outcomes in chimeric antigen receptor (CAR) T cell therapy.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Large B cell lymphomas (LBCL) are heterogeneous lymphoid malignancies.
- Tumor microenvironments significantly influence LBCL pathogenesis and progression.
- Understanding cellular composition is crucial for targeted therapies.
Purpose of the Study:
- To comprehensively characterize cellular diversity within LBCL tumors.
- To identify recurring patterns of cell co-occurrence, termed lymphoma microenvironment archetype profiles (LymphoMAPs).
- To investigate the relationship between LymphoMAPs, cell-cell communication, and clinical outcomes, particularly following CAR T cell therapy.
Main Methods:
- Single-nucleus multiome profiling was performed on 232 tumor and control biopsies.
- Analysis focused on lymphoid, myeloid, and non-hematopoietic cell compartments.
- Lymphoma microenvironment archetypes (LymphoMAPs) were defined based on cell subset frequencies.
Main Results:
- Three stereotypical LymphoMAPs were identified: FMAC (fibroblasts, macrophages), LN (lymph node architecture), and TEX (exhausted T cells).
- Distinct cell-cell communication patterns were associated with each LymphoMAP, influencing T cell exclusion, support, or suppression.
- LymphoMAPs demonstrated significant associations with clinical outcomes after CD19 CAR T cell therapy.
Conclusions:
- LBCL tumor microenvironments exhibit distinct, reproducible archetypes (LymphoMAPs).
- These archetypes are shaped by specific cell-cell communication networks.
- LymphoMAPs serve as predictive biomarkers for patient response to CAR T cell therapy in LBCL.
Abstract:
Large B cell lymphomas (LBCL) are clinically and biologically heterogeneous lymphoid malignancies with complex microenvironments that are central to disease etiology. Here, we have employed single-nucleus multiome profiling of 232 tumor and control biopsies to characterize diverse cell types and subsets that are present in LBCL tumors, effectively capturing the lymphoid, myeloid, and non-hematopoietic cell compartments. Cell subsets co-occurred in stereotypical lymphoma microenvironment archetype profiles (LymphoMAPs) defined by; (1) a sparsity of T cells and high frequencies of cancer-associated fibroblasts and tumor-associated macrophages (FMAC); (2) lymph node architectural cell types with naive and memory T cells (LN); or (3) activated macrophages and exhausted CD8+ T cells (TEX). Divergent patterns of cell-cell communication underpinned the transcriptional phenotypes of archetype-defining cell subsets resulting in exclusion, support, or suppression of T cells, respectively. Consistent with this, LymphoMAPs were associated with significantly different clinical outcomes following CD19 chimeric antigen receptor (CAR) T cell therapy.
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