Distinct follicular T cell subsets regulate lymphoma progression and outcomes

Yoshiaki Abe¹, Junko Zenkoh², Akinori Kanai², Daisuke Ikeda³, Daisuke Kaji⁴, Aya Sawa⁵, Ryota Matsuoka⁶, Kei Asayama⁷, Rikako Tabata³, Ryota Ishii⁸, Manabu Fujisawa⁹, Kenichi Makishima¹⁰, Sakurako Suma¹⁰, Yasuhito Suehara¹¹, Keiichiro Hattori¹¹, Tatsuhiro Sakamoto¹¹, Hidekazu Nishikii¹¹, Chikashi Yoshida¹², Hiroko Bando¹³, Ayako Suzuki², Yasunori Ota¹⁴, Yoshihito Otsuka¹⁵, Daisuke Matsubara⁶, Kosei Matsue³, Shigeru Chiba¹¹, Christian Steidl¹⁶, Yutaka Suzuki², Mamiko Sakata-Yanagimoto¹⁷

Affiliations

¹ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan. Electronic address: yoshiakiabe1018@gmail.com.
² Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
³ Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, Kamogawa, Japan.
⁴ Department of Hematology, Toranomon Hospital, Tokyo, Japan.
⁵ Department of Breast-Thyroid-Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.
⁶ Department of Pathology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
⁷ Department of Diagnostic Pathology, University of Tsukuba Hospital, Tsukuba, Japan.
⁸ Department of Biostatistics, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
⁹ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Division of Lymphoma Pathophysiology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan.
¹⁰ Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.
¹¹ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.
¹² Department of Hematology, NHO Mito Medical Center, Ibaraki, Japan.
¹³ Department of Breast and Endocrine Surgery, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁴ Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁵ Department of Clinical Laboratory, Kameda Medical Center, Kamogawa, Japan.
¹⁶ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Division of Lymphoma Pathophysiology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan; Division of Advanced Hemato-Oncology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan. Electronic address: sakatama@md.tsukuba.ac.jp.

PMID: 40614737
DOI: 10.1016/j.ccell.2025.06.013

Free article

Distinct follicular T cell subsets regulate lymphoma progression and outcomes

Yoshiaki Abe et al. Cancer Cell. 2025.

Free article

. 2025 Oct 13;43(10):1850-1865.e11.

doi: 10.1016/j.ccell.2025.06.013. Epub 2025 Jul 3.

Authors

Affiliations

¹ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan. Electronic address: yoshiakiabe1018@gmail.com.
² Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
³ Division of Hematology/Oncology, Department of Internal Medicine, Kameda Medical Center, Kamogawa, Japan.
⁴ Department of Hematology, Toranomon Hospital, Tokyo, Japan.
⁵ Department of Breast-Thyroid-Endocrine Surgery, University of Tsukuba Hospital, Tsukuba, Japan.
⁶ Department of Pathology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
⁷ Department of Diagnostic Pathology, University of Tsukuba Hospital, Tsukuba, Japan.
⁸ Department of Biostatistics, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
⁹ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Division of Lymphoma Pathophysiology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan.
¹⁰ Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.
¹¹ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan.
¹² Department of Hematology, NHO Mito Medical Center, Ibaraki, Japan.
¹³ Department of Breast and Endocrine Surgery, Institute of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁴ Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹⁵ Department of Clinical Laboratory, Kameda Medical Center, Kamogawa, Japan.
¹⁶ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada; Division of Lymphoma Pathophysiology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Department of Hematology, Institute of Medicine, University of Tsukuba, Tsukuba, Japan; Department of Hematology, University of Tsukuba Hospital, Tsukuba, Japan; Division of Advanced Hemato-Oncology, Transborder Medical Research Center, University of Tsukuba, Tsukuba, Japan. Electronic address: sakatama@md.tsukuba.ac.jp.

PMID: 40614737
DOI: 10.1016/j.ccell.2025.06.013

Abstract

Follicular lymphoma (FL) is characterized by the expansion of neoplastic follicle structures and is suggested to have a distinctive form of T cell immunity. However, the heterogeneity and role of follicular T cells beyond T follicular helper (T_FH) cells remain largely unexplored in FL. Here, we performed multi-omics analyses of follicular T cells in FL leveraging pan-cancer single-cell mapping, spatially resolved single-cell transcriptomics and multiplex protein profiling, and functional characterization. We identified transcriptionally and spatially distinct non-T_FH follicular T cell subsets that expand in FL. These subsets exhibit enhanced anti-tumorigenic properties and form unique spatial niches. Their phenotypes were replicated under interleukin-21-predominant conditions, revealing discrete self-regulatory cellular ecosystems that generate these subsets and may underlie FL clinical behaviors. Furthermore, these subsets robustly stratify FL prognoses, independently of existing prognostic markers. Our findings highlight previously unrecognized immunity that could advance our understanding of lymphoma and improve patient management.

Keywords: T cell; follicular cytotoxic T cell; follicular lymphoma; follicular regulatory T cell; pan-cancer; prognosis; single cell; spatial; stem-like T cell; tumor microenvironment.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Distinct follicular T cell subsets regulate lymphoma progression and outcomes

Affiliations

Distinct follicular T cell subsets regulate lymphoma progression and outcomes

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Miscellaneous