CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer
Masayo Ukita, … , Hideki Ueno, Masaki Mandai
Masayo Ukita, … , Hideki Ueno, Masaki Mandai
Published May 12, 2022
Citation Information: JCI Insight. 2022;7(12):e157215. https://doi.org/10.1172/jci.insight.157215.
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Research Article Immunology Oncology

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

Abstract

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLS 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 it was a favorable prognostic factor for patients with HGSC. 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 TLS. CXCL13 expression was predominantly coincident with CD4+ T cells in TLS and CD8+ T cells in TILs, and it shifted from CD4+ T cells to CD21+ follicular DCs as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLS 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 TLS facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.

Authors

Masayo Ukita, Junzo Hamanishi, Hiroyuki Yoshitomi, Koji Yamanoi, Shiro Takamatsu, Akihiko Ueda, Haruka Suzuki, Yuko Hosoe, Yoko Furutake, Mana Taki, Kaoru Abiko, Ken Yamaguchi, Hidekatsu Nakai, Tsukasa Baba, Noriomi Matsumura, Akihiko Yoshizawa, Hideki Ueno, Masaki Mandai

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Figure 5

TGF-β promotes the production of CXCL13.

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TGF-β promotes the production of CXCL13. (A) Correlation between CXCL13 ...
(A) Correlation between CXCL13 and TGF-β1 expression in TCGA (n = 217) and KOV (n = 28). Correlation was determined by Spearman’s correlation test. (B) Human naive CD4+ and CD8+ T cells from a healthy donor were differentiated by TCR stimulation and TGF-β1 in the presence or absence of a TGF signal inhibitor, SB431542. The proportion of CXCL13+ cells was determined by flow cytometry. Data are shown as the mean ± SEM (n = 3–4). Statistical significance was determined by 2-tailed Student’s t test. *P < 0.05, **P < 0.01, and ***P < 0.001. (C) The concentration of TGF-β1 in conditioned medium obtained from 3 human ovarian cancer cell lines was measured by ELISA. Data are shown as the mean ± SEM (n = 3). (D) Human naive CD4+ and CD8+ T cells from a healthy donor were differentiated with TCR stimulation and conditioned medium obtained from 3 human ovarian cancer cell lines in the presence or absence of a TGF signal inhibitor, SB431542. The proportion of CXCL13+ cells was determined by flow cytometry. Data are shown as the mean ± SEM (n = 3). (E–G) Human naive CD4+ and CD8+ T cells from a healthy donor were differentiated with TCR stimulation and the indicated cytokines. The proportion of CXCL13+ cells was determined by flow cytometry (E). The concentration of CXCL13 in the culture supernatant was measured by ELISA (F). Data are shown as the mean ± SEM (n = 3–4). Statistical significance was determined by 2-tailed Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Representative dot plots of PD-1 (upper row), CXCR5 (lower row), and intracellular CXCL13 in healthy human naive CD4+ T cells are shown (G).