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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/jci.insight.157215

CXCL13-producing CD4+ T cells accumulate in early phase of tertiary lymphoid structures in ovarian cancer

Masayo Ukita,1 Junzo Hamanishi,1 Hiroyuki Yoshitomi,2 Koji Yamanoi,1 Shiro Takamatsu,1 Akihiko Ueda,1 Haruka Suzuki,1 Yuko Hosoe,1 Yoko Furutake,1 Mana Taki,1 Kaoru Abiko,3 Ken Yamaguchi,1 Hidekatsu Nakai,4 Tsukasa Baba,5 Noriomi Matsumura,4 Akihiko Yoshizawa,6 Hideki Ueno,2 and Masaki Mandai7

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Ukita, M. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Hamanishi, J. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Yoshitomi, H. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Yamanoi, K. in: JCI | PubMed | Google Scholar

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Takamatsu, S. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Ueda, A. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Suzuki, H. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Hosoe, Y. in: JCI | PubMed | Google Scholar

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Furutake, Y. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Taki, M. in: JCI | PubMed | Google Scholar

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Abiko, K. in: JCI | PubMed | Google Scholar

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Yamaguchi, K. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Nakai, H. in: JCI | PubMed | Google Scholar

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Baba, T. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Matsumura, N. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Yoshizawa, A. in: JCI | PubMed | Google Scholar

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Ueno, H. in: JCI | PubMed | Google Scholar |

1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

2Department of immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan

3Department of Obstetrics and Gynecology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan

4Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan

5Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

6Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan

7Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medinine, Kyoto, Japan

Find articles by Mandai, M. in: JCI | PubMed | Google Scholar

Published May 12, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.157215.
Copyright © 2022, Ukita et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 12, 2022 - Version history
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Abstract

Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLSs are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and was a favorable prognostic factor for HGSC patients. Coexistence of CD8+ T cells and B-cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLSs. CXCL13 expression was predominantly coincident with CD4+ T cells in TLSs and CD8+ T cells in TILs, and shifted from CD4+ T cells to CD21+ follicular dendritic cells as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLSs and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLSs facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.

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