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. 2025 Jul 14;43(7):1347-1364.e13.
doi: 10.1016/j.ccell.2025.06.002. Epub 2025 Jun 18.

Large B cell lymphoma microenvironment archetype profiles

Xubin Li  1 , Kartik Singhal  2 , Qing Deng  3 , Dai Chihara  3 , David Russler-Germain  4 , R Andrew Harkins  3 , Jared Henderson  3 , Kotaro Arita  3 , Atish Kizhakeyil  3 , Ryan Sun  5 , Priya Lakra  3 , Usama Hussein  3 , Jennifer A Foltz  4 , Ashley Wilson  3 , Evelyn Schmidt  2 , Imran Nizamuddin  2 , Tommy Dinh  3 , Akhil Kesaraju  2 , Mark P Hamilton  3 , Carl Allen  6 , Maher K Gandhi  7 , Joshua Tobin  7 , Aixiang Jiang  8 , Laura Hilton  8 , David W Scott  9 , Francisco Vega  10 , Christopher R Flowers  1 , Jason R Westin  1 , Obi L Griffith  11 , Todd A Fehniger  12 , Malachi Griffith  11 , Michael R Green  13
Affiliations

Large B cell lymphoma microenvironment archetype profiles

Xubin Li et al. Cancer Cell. .

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.

Keywords: CAR T cell; lymphoma; microenvironment; single cell RNA sequencing.

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Conflict of interest statement

Declaration of interests M.R.G. reports research funding from Sanofi, Kite/Gilead, Abbvie and Allogene; consulting for Abbvie and Allogene; advisory board for Bristol Myers Squibb, Arvinas and Johnson & Johnson; honoraria from BMS, Daiichi Sankyo and DAVA Oncology; and stock ownership of KDAc Therapeutics. |T.A.F. is an inventor on patent/patent applications (15/983,275, 62/963,971, and PCT/US2019/060005) held by Washington University; has equity in Wugen, Orca Bio, and Indapta Therapeutics; research funding from HCW Biologics Inc., Wugen Inc., Affimed, AI Proteins and the NIH; consulting (SAB) for Affimed and AI Proteins. C.R.F. reports consulting for Abbvie, Bayer, BeiGene, Celgene, Denovo Biopharma, Foresight Diagnostics, Genentech/Roche, Genmab, Gilead, Karyopharm, N-Power Medicine, Pharmacyclics/Janssen, SeaGen, Spectrum; Stock options in Foresight Diagnostics, N-Power Medicine; Research funding from 4D, Abbvie, Acerta, Adaptimmune, Allogene, Amgen, Bayer, Celgene, Cellectis EMD, Gilead, Genentech/Roche, Guardant, Iovance, Janssen Pharmaceutical, Kite, Morphosys, Nektar, Novartis, Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor, Ziopharm, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research.| J.R.W. reports research Funding/Advisory Board from Abbvie, ADC therapeutics, Allogene, AstraZeneca, BMS, Genentech, Janssen, Kite/Gilead, Morphosys/Incyte, Novartis, Nurix, Pfizer, Regeneron. C.A. reports research funding from Genentech and advisory boards for OPNA, Electra and SOBI. D.W.S. reports consultancy for Abbvie, AstraZeneca, GenMab, Incyte, Roche, Veracyte; Research funding from Roche/Genentech; named inventor on patents describing the use of gene expression to subtype aggressive B cell lymphoma, including on licensed to nanoString Technologies.

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