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<p>Glioblastoma (GBM) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that constrains the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Here, we show that surgical resection in both male mice and human GBM ex vivo induces a rapid and sustained remodeling of the TME, marked by upregulation of TREM2 in myeloid cells followed by emergence of T cell exhaustion-like phenotypes. In male mice, targeting TREM2 reshapes the perioperative TME and potentiates tumor antigen-specific CAR-T cell responses, improving intratumoral persistence, proliferation, and effector differentiation, and resulting in enhanced survival. In parallel, we identify the timing of CAR-T cell administration as a critical determinant of therapeutic outcome, with neoadjuvant outperforming adjuvant treatment by preserving CAR-T cell effector function in mice. These findings establish perioperative myeloid cell remodeling and treatment timing as key determinants of CAR-T cell efficacy in GBM.</p>

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Perioperative myeloid cell remodeling shapes CAR-T cell efficacy in glioblastoma

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月31日

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  • Martin Pedard,
  • Luis Castillo Cantero,
  • Ali Ghasemi,
  • Eliana Marinari,
  • Caterina Mollica,
  • Suzel Davanture,
  • Julie Pernot,
  • Valérie Widmer,
  • Doron Merkler,
  • Kristof Egervari,
  • Kark Schaller,
  • Philippe Bijlenga,
  • Andrea Bartoli,
  • Shahan Momjian,
  • Mikael J. Pittet,
  • Valérie Dutoit,
  • Denis Migliorini

摘要

Glioblastoma (GBM) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that constrains the efficacy of chimeric antigen receptor (CAR)-T cell therapy. Here, we show that surgical resection in both male mice and human GBM ex vivo induces a rapid and sustained remodeling of the TME, marked by upregulation of TREM2 in myeloid cells followed by emergence of T cell exhaustion-like phenotypes. In male mice, targeting TREM2 reshapes the perioperative TME and potentiates tumor antigen-specific CAR-T cell responses, improving intratumoral persistence, proliferation, and effector differentiation, and resulting in enhanced survival. In parallel, we identify the timing of CAR-T cell administration as a critical determinant of therapeutic outcome, with neoadjuvant outperforming adjuvant treatment by preserving CAR-T cell effector function in mice. These findings establish perioperative myeloid cell remodeling and treatment timing as key determinants of CAR-T cell efficacy in GBM.