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<p>Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8<sup>+</sup> T cells that eradicate established murine tumors promote expansion of host CD8<sup>+</sup> T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8<sup>+</sup> T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8<sup>+</sup> T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8<sup>+</sup> T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.</p>

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Lymphodepleting preconditioning impairs host antitumor immunity induced by adoptive T cell therapy in mouse models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月31日

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  • Diego Figueroa,
  • Juan Pablo Vega,
  • Andrés Hernández-Oliveras,
  • Felipe Ardiles,
  • Sofía Hidalgo,
  • Ximena López,
  • Vicente Saavedra,
  • Catalina Bustamante,
  • Daniela Malavé,
  • Felipe Flores,
  • Felipe Gálvez-Cancino,
  • Hugo Gonzalez,
  • Manuel Varas-Godoy,
  • Maria Rosa Bono,
  • Fabiola Osorio,
  • Vincenzo Borgna,
  • Alvaro Lladser

摘要

Adoptive T cell therapy (ACT) is effective against hematologic cancers, but the mechanisms underlying durable responses in solid tumors remain unclear. We show that adoptively transferred CD8+ T cells that eradicate established murine tumors promote expansion of host CD8+ T cells exhibiting tumor-reactive and tissue-resident phenotypes that contribute to tumor elimination. Mechanistically, tumor necrosis factor (TNF) from transferred cells induces dendritic cell (DC)-dependent expansion of host CD8+ T cells, conferring protection against ACT-resistant tumor cells lacking the targeted antigen. Lymphodepleting preconditioning promotes expansion of transferred cells and primary tumor eradication but impairs host antitumor immunity and abrogates protection against ACT-resistant tumors. In human tumors, increased TNF/DC/CD8+ T cell profiles correlate with favorable ACT responses and improved survival. These findings reveal a TNF-dependent interplay between transferred and host CD8+ T cells underlying durable antitumor immunity that is impaired by lymphodepleting preconditioning in mouse models, suggesting an underappreciated mechanism of ACT resistance.