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<p>Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8<sup>+</sup> T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4<sup>+</sup> T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.</p>

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In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月11日

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  • Marco Notaro,
  • Maristella Borghetti,
  • Chiara Bresesti,
  • Giovanna Giacca,
  • Thomas Kerzel,
  • Carl Mirko Mercado,
  • Stefano Beretta,
  • Marco Monti,
  • Ivan Merelli,
  • Silvia Iaia,
  • Marco Genua,
  • Andrea Annoni,
  • Tamara Canu,
  • Patrizia Cristofori,
  • Sara Degl’Innocenti,
  • Francesca Sanvito,
  • Paola Maria Vittoria Rancoita,
  • Renato Ostuni,
  • Silvia Gregori,
  • Luigi Naldini,
  • Mario Leonardo Squadrito

摘要

Despite recent progress in cancer treatment, liver metastases persist as an unmet clinical need. Here, we show that arming liver and tumor-associated macrophages in vivo to co-express tumor antigens (TAs), IFNα, and IL-12 unleashes robust anti-tumor immune responses, leading to the regression of liver metastases. Mechanistically, in vivo armed macrophages expand tumor reactive CD8+ T cells, which acquire features of progenitor exhausted T cells and kill cancer cells independently of CD4+ T cell help. IFNα and IL-12 produced by armed macrophages reprogram antigen presenting cells and rewire cellular interactions, rescuing tumor reactive T cell functions. In vivo armed macrophages trigger anti-tumor immunity in distinct liver metastasis mouse models of colorectal cancer and melanoma, expressing either surrogate tumor antigens, naturally occurring neoantigens or tumor-associated antigens. Altogether, our findings support the translational potential of in vivo armed liver macrophages to expand and rejuvenate tumor reactive T cells for the treatment of liver metastases.