Perioperative myeloid cell remodeling shapes CAR-T cell efficacy in glioblastoma
- 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
2026-07-31
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.