Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma

Yibo Dai; Atish Kizhakeyil; Dai Chihara; Xubin Li; Yunhe Liu; Tania Patricia Sainz Zuniga; Ashley Wilson; Jared Henderson; Daniil Vibe; Arman Petrosyants; Connor Jacobson; Alexander Sarachakov; Krystle Nomie; Kirill Kryukov; Aleksander Bagaev; Ayushi Chauhan; Jason R. Westin; Christopher R. Flowers; Francisco Vega; Linghua Wang; Michael R. Green

doi:10.1038/s41588-025-02353-5

Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma

Yibo Dai (Co-first Author)
, Atish Kizhakeyil (Co-first Author)
, Dai Chihara
, Xubin Li
, Yunhe Liu
, Tania Patricia Sainz Zuniga
, Ashley Wilson
, Jared Henderson
, Daniil Vibe
, Arman Petrosyants
, Connor Jacobson
, Alexander Sarachakov
, Krystle Nomie
, Kirill Kryukov
, Aleksander Bagaev
, Ayushi Chauhan
, Jason R. Westin
, Christopher R. Flowers
, Francisco Vega
, Linghua Wang^*

Michael R. Green^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

13 Citations (Scopus)

Abstract

Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B cells and bore transcriptional hallmarks of activation and effector function, suggesting that they may be primed for anti-tumor immunity. Spatial characterization of the DLBCL immune microenvironment, therefore, reveals cellular niches that foster divergent patterns of cell–cell interactions contributing to the phenotypic heterogeneity of both niche-resident tumor and immune cells.

© The Author(s) 2025

Original language	English
Pages (from-to)	2715-2727
Number of pages	13
Journal	Nature Genetics
Volume	57
Issue number	11
Online published	21 Oct 2025
DOIs	https://doi.org/10.1038/s41588-025-02353-5
Publication status	Published - Nov 2025
Externally published	Yes

Funding

This work was chiefly supported by the Futcher family. M.R.G. is a Scholar of the Leukemia and Lymphoma Society. A.K. is supported by a Lymphoma Research Foundation fellowship. L.W. was in part supported by the James P. Allison Institute and the Institute for Data Science in Oncology at the University of Texas MD Anderson Cancer Center.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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This full text is made available under CC-BY-NC-ND 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/

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Dai, Y., Kizhakeyil, A., Chihara, D., Li, X., Liu, Y., Sainz Zuniga, T. P., Wilson, A., Henderson, J., Vibe, D., Petrosyants, A., Jacobson, C., Sarachakov, A., Nomie, K., Kryukov, K., Bagaev, A., Chauhan, A., Westin, J. R., Flowers, C. R., Vega, F., ... Green, M. R. (2025). Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma. Nature Genetics, 57(11), 2715-2727. https://doi.org/10.1038/s41588-025-02353-5

@article{fe609efccd274a6cb0a167c97c6e8a8c,

title = "Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma",

abstract = "Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B cells and bore transcriptional hallmarks of activation and effector function, suggesting that they may be primed for anti-tumor immunity. Spatial characterization of the DLBCL immune microenvironment, therefore, reveals cellular niches that foster divergent patterns of cell–cell interactions contributing to the phenotypic heterogeneity of both niche-resident tumor and immune cells. {\textcopyright} The Author(s) 2025",

author = "Yibo Dai and Atish Kizhakeyil and Dai Chihara and Xubin Li and Yunhe Liu and \{Sainz Zuniga\}, \{Tania Patricia\} and Ashley Wilson and Jared Henderson and Daniil Vibe and Arman Petrosyants and Connor Jacobson and Alexander Sarachakov and Krystle Nomie and Kirill Kryukov and Aleksander Bagaev and Ayushi Chauhan and Westin, \{Jason R.\} and Flowers, \{Christopher R.\} and Francisco Vega and Linghua Wang and Green, \{Michael R.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = nov,

doi = "10.1038/s41588-025-02353-5",

language = "English",

volume = "57",

pages = "2715--2727",

journal = "Nature Genetics",

issn = "1061-4036",

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Dai, Y, Kizhakeyil, A, Chihara, D, Li, X, Liu, Y, Sainz Zuniga, TP, Wilson, A, Henderson, J, Vibe, D, Petrosyants, A, Jacobson, C, Sarachakov, A, Nomie, K, Kryukov, K, Bagaev, A, Chauhan, A, Westin, JR, Flowers, CR, Vega, F, Wang, L & Green, MR 2025, 'Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma', Nature Genetics, vol. 57, no. 11, pp. 2715-2727. https://doi.org/10.1038/s41588-025-02353-5

Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma. / Dai, Yibo (Co-first Author); Kizhakeyil, Atish (Co-first Author); Chihara, Dai et al.
In: Nature Genetics, Vol. 57, No. 11, 11.2025, p. 2715-2727.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma

AU - Dai, Yibo

AU - Kizhakeyil, Atish

AU - Chihara, Dai

AU - Li, Xubin

AU - Liu, Yunhe

AU - Sainz Zuniga, Tania Patricia

AU - Wilson, Ashley

AU - Henderson, Jared

AU - Vibe, Daniil

AU - Petrosyants, Arman

AU - Jacobson, Connor

AU - Sarachakov, Alexander

AU - Nomie, Krystle

AU - Kryukov, Kirill

AU - Bagaev, Aleksander

AU - Chauhan, Ayushi

AU - Westin, Jason R.

AU - Flowers, Christopher R.

AU - Vega, Francisco

AU - Wang, Linghua

AU - Green, Michael R.

PY - 2025/11

Y1 - 2025/11

N2 - Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B cells and bore transcriptional hallmarks of activation and effector function, suggesting that they may be primed for anti-tumor immunity. Spatial characterization of the DLBCL immune microenvironment, therefore, reveals cellular niches that foster divergent patterns of cell–cell interactions contributing to the phenotypic heterogeneity of both niche-resident tumor and immune cells. © The Author(s) 2025

AB - Diffuse large B cell lymphomas (DLBCLs) are a heterogeneous group of malignancies that can arise in lymph nodes or extranodal locations, including immune-privileged sites. Here, we applied highly multiplexed spatial transcriptomics and proteomics together with genomic profiling to characterize the immune microenvironment architecture of 78 DLBCL tumors. We define seven distinct cellular niches, each characterized by unique cellular compositions, spatial organizations and patterns of intercellular communication associated with niche-specific phenotypes of both T cells and tumor B cells. Among these, DLBCLs from immune-privileged sites showed abundant T cell infiltration into diffuse niches, where immune cells were intermixed with tumor B cells and bore transcriptional hallmarks of activation and effector function, suggesting that they may be primed for anti-tumor immunity. Spatial characterization of the DLBCL immune microenvironment, therefore, reveals cellular niches that foster divergent patterns of cell–cell interactions contributing to the phenotypic heterogeneity of both niche-resident tumor and immune cells. © The Author(s) 2025

UR - https://www.scopus.com/pages/publications/105019533375

U2 - 10.1038/s41588-025-02353-5

DO - 10.1038/s41588-025-02353-5

M3 - RGC 21 - Publication in refereed journal

C2 - 41120574

AN - SCOPUS:105019533375

SN - 1061-4036

VL - 57

SP - 2715

EP - 2727

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Multi-modal spatial characterization of tumor immune microenvironments identifies targetable inflammatory niches in diffuse large B cell lymphoma

Abstract

Funding

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