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Review ArticleReview

Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism, functional regulation, and immunotherapeutic strategies

Hua Zhao, Hao Wang, Qiuru Zhou and Xiubao Ren
Cancer Biology & Medicine November 2021, 18 (4) 981-991; DOI: https://doi.org/10.20892/j.issn.2095-3941.2021.0029
Hua Zhao
1Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China
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Hao Wang
1Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China
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Qiuru Zhou
1Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China
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Xiubao Ren
1Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China
2Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin 300060, China
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    Figure 1

    The immune regulation in TLSs.

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    Table 1

    The immune characteristics of tertiary lymphoid structures in cancers

    Characteristic detecting markersSubpopulation markersPrognosesReference
    B cell zoneCD20+B cellsNaïve B cells: CD19+CD20+IgD+No evaluation13,17,18
    Memory B cells: CD19+CD20+CD27+No evaluation13,17,18
    PCs: CD20−CD27+CD38+CD138+Favorable13,19,20
    Plasma blasts: CD20−CD27+ CD38+Favorable13,19,20
    FDC: CD21+, CD35+, CD23+, all the markers also expressed on B cellsFavorable13,19,20
    Tfh: CD4+CXCR5+Bcl6+Favorable19,20,36
    Tfr: CD4+CXCR5+foxp3+No evaluation68,69
    GC: Bcl-6+CD20+B cells, or Ki67+CD20+ B cellsFavorable12,13,18
    Breg: IL-10+IgA+CD19+Unfavorable57,58
    Macrophage: CD68+Unfavorable64
    T cell zoneCD3+T cells, orNaïve T cell: CCR7+CD45RO−T cellsNo evaluation12
    CD4+T cells orMemory T cells: CD45RO+CD45RA−T cellsFavorable12
    CD8+T cellsTregs: CD4+foxp3+T cellsUnfavorable13,61
    CTL: CD8+ Granzyme B+ T cellsFavorable12,13,61
    Helper T cells: T-bet+Th1Favorable12,15
        GATA3+ Th2Unfavorable64
        RORγt+ Th17No evaluation64
    DC: LAMP3+ or CD83+ or CD86+Favorable12,13
    Others:
    HEVPNAdPNAd or MECA79Favorable17
    ChemokinesCXCL13/CXCL12CCL-2,3,4,5,8,18,19,21; CXCL-9, 10,11,12,13Favorable16,17,18
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    Table 2

    Maturity classifications of tertiary lymphoid structures

    Definition and cellular compositionMarker cell subsets
    E-TLSDense lymphocytic aggregates without FDCsCD4+ and CD8+T cells, CD20+B cells, and occasional DCs
    PFL-TLSHaving more dense lymphocytic aggregates with FDCs but no GC reactionCD4+ and CD8+T cells, CD20+B cells, and/or occasional DCs, and FDC
    SFL-TLSHaving dense lymphocytic aggregates with FDCs and GC reactionBcl6+or Ki67+CD20+B cells, CD38+ and/or CD138+ CD19+B cells
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Cancer Biology & Medicine: 18 (4)
Cancer Biology & Medicine
Vol. 18, Issue 4
1 Nov 2021
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Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism, functional regulation, and immunotherapeutic strategies
Hua Zhao, Hao Wang, Qiuru Zhou, Xiubao Ren
Cancer Biology & Medicine Nov 2021, 18 (4) 981-991; DOI: 10.20892/j.issn.2095-3941.2021.0029

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Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism, functional regulation, and immunotherapeutic strategies
Hua Zhao, Hao Wang, Qiuru Zhou, Xiubao Ren
Cancer Biology & Medicine Nov 2021, 18 (4) 981-991; DOI: 10.20892/j.issn.2095-3941.2021.0029
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  • Article
    • Abstract
    • Introduction
    • The composition of TLSs
    • TLS location and its prognostic impact on cancer patients
    • Maturation classification of TLSs and their effects on the prognoses of cancer patients
    • Antitumor mechanism of TLSs
    • Immunosuppressive factors in TLSs
    • TLS induction of reprogramming of the TME suggests novel antitumor directions
    • Conclusions
    • Grant support
    • Acknowledgments
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Keywords

  • Tertiary lymphoid structure
  • tumor microenvironment
  • immunotherapy
  • B cells
  • T cells

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