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.