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<p>B cell-rich tertiary lymphoid structures (TLS) are associated with favorable prognosis and positive response to immunotherapy in cancer. Here we show that simultaneous activation of innate immune effectors, STING and lymphotoxin-β receptor (LTβR), results in CD8<sup>+</sup> T cell-dependent tumor suppression while inducing high endothelial venule development and germinal center-like B cell responses in tumors to generate functional TLS in a T cell-dependent manner. In a neoadjuvant setting, activation of STING and LTβR by their agonists effectively immunized mice against tumor recurrence, leading to long-term survival. STING activation alone was insufficient for inducing B cell-containing TLS or eliciting long-term therapeutic effects. However, when combined with LTβR activation, it improved the fitness of TLS with B cell expansion and maturation to IgG-producing long-lived plasma cells and memory cells, increased CD4<sup>+</sup> T cell recruitment and memory CD8<sup>+</sup> T cell expansion, and shifted the T<sub>H</sub>2/T<sub>H</sub>17 balance, resulting in the potentiation of humoral and cellular immunity against tumors. These findings suggest a therapeutic approach of simultaneously activating STING and lymphotoxin pathways.</p>

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Simultaneous STING and lymphotoxin-β receptor activation induces B cell responses in tertiary lymphoid structures to potentiate antitumor immunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月2日

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  • Junko Sawada,
  • Yasuhiro Kikuchi,
  • Maxwell Duah,
  • Jose Luis Herrera,
  • Fumiaki Kanamori,
  • Krisztian Csomos,
  • Tomoko Stansel,
  • Nobuyoshi Hiraoka,
  • Masayuki Yoshida,
  • Jolan Walter,
  • Carl F. Ware,
  • Masanobu Komatsu

摘要

B cell-rich tertiary lymphoid structures (TLS) are associated with favorable prognosis and positive response to immunotherapy in cancer. Here we show that simultaneous activation of innate immune effectors, STING and lymphotoxin-β receptor (LTβR), results in CD8+ T cell-dependent tumor suppression while inducing high endothelial venule development and germinal center-like B cell responses in tumors to generate functional TLS in a T cell-dependent manner. In a neoadjuvant setting, activation of STING and LTβR by their agonists effectively immunized mice against tumor recurrence, leading to long-term survival. STING activation alone was insufficient for inducing B cell-containing TLS or eliciting long-term therapeutic effects. However, when combined with LTβR activation, it improved the fitness of TLS with B cell expansion and maturation to IgG-producing long-lived plasma cells and memory cells, increased CD4+ T cell recruitment and memory CD8+ T cell expansion, and shifted the TH2/TH17 balance, resulting in the potentiation of humoral and cellular immunity against tumors. These findings suggest a therapeutic approach of simultaneously activating STING and lymphotoxin pathways.