Regulatory T cell depletion promotes myeloid cell activation and glioblastoma response to anti-PD1 and tumor-targeting antibodies
Glioblastoma is invariably lethal and responds poorly to immune checkpoint blockade. Here, we examined the impact of regulatory T (Treg) cell depletion on glioblastoma progression and immunotherapy responsiveness. In human glioblastoma, elevated Treg cell signatures correlated with poorer survival outcomes, with these cells expressing high levels of CD25. In Nf1<sup>-/-</sup>Pten<sup>-/-</sup>EGFRvIII<sup>+</sup> glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25<sup>NIB</sup>) antibody depleted Treg cells and promoted CD8<sup>+</sup> T cell clonal expansion and partial tumor control, further enhanced by programmed cell death-1 (PD1)-blockade. Treg cell depletion induced interferon-γ (IFN-γ)-dependent tumor microenvironment remodeling, increasing Fcγ receptor (FcγR) expression on intratumoral myeloid cells and enhancing phagocytosis. Combination of anti-CD25<sup>NIB</sup> with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25<sup>NIB</sup> treatment of glioblastoma patient-derived tumor fragments effectively depleted Treg cells and activated CD8<sup>+</sup> T cells. These findings underscore the therapeutic relevance of Treg targeting in glioblastoma and unveil potent combination strategies for anti-CD25<sup>NIB</sup> based on innate cell activation.
Authors
- Simona Parrinello (ORCID: https://orcid.org/0000-0003-0820-6292)
- Fatemeh Vahid Dastjerdi
- Gordon Beattie
- Aditya Shroff
- Sergio A. Quezada (ORCID: https://orcid.org/0000-0002-9763-1700)
- Kevin Litchfield (ORCID: https://orcid.org/0000-0002-3725-0914)
- Martin Pulé (ORCID: https://orcid.org/0000-0002-8347-9867)
- Alexander P. Simpson (ORCID: https://orcid.org/0000-0003-3439-2236)
- Enrique Miranda (ORCID: https://orcid.org/0000-0003-3361-3957)
- Felipe Gálvez‐Cancino (ORCID: https://orcid.org/0000-0001-8417-1891)
- Melanie Clements (ORCID: https://orcid.org/0000-0001-5265-8830)
- A. Lee
- Teerapon Sahwangarrom
- Enrico Lugli (ORCID: https://orcid.org/0000-0002-1964-7678)
- Beatrice Claudia Cianciotti (ORCID: https://orcid.org/0000-0002-1337-5915)
- Mariela Navarrete
- Steven M. Pollard (ORCID: https://orcid.org/0000-0001-6428-0492)
- Francesco Nannini (ORCID: https://orcid.org/0000-0001-9589-5107)
- Cristóbal Costoya (ORCID: https://orcid.org/0000-0001-6573-3959)
- Kane Foster (ORCID: https://orcid.org/0000-0002-0330-8305)
- Nicholas McGranahan (ORCID: https://orcid.org/0000-0001-9537-4045)
- Despoina Karagianni (ORCID: https://orcid.org/0000-0002-8605-5808)
- Vellareddy Anantharam
- Samuel Marguerat (ORCID: https://orcid.org/0000-0002-2402-3165)
- Kerry Chester (ORCID: https://orcid.org/0000-0002-3093-3130)
- Dimitrios A. Garyfallos (ORCID: https://orcid.org/0000-0003-1338-0682)
- Imran Uddin (ORCID: https://orcid.org/0000-0003-0736-3149)
- Shahida Sheraz
- Paul Martin Brennan (ORCID: https://orcid.org/0000-0002-7347-830X)
- Claudia Garcia-Diaz (ORCID: https://orcid.org/0000-0003-0867-5339)
- Leanne Bradley (ORCID: https://orcid.org/0000-0002-3331-9689)
- Simone Puccio (ORCID: https://orcid.org/0000-0003-4007-4365)
- Álvaro Lladser (ORCID: https://orcid.org/0000-0002-5576-1478)
- James L. Reading (ORCID: https://orcid.org/0000-0001-5381-978X)
- Gerasimos-Theodoros Mastrokalos
- Jiali Liu (ORCID: https://orcid.org/0000-0002-8732-6139)
- Robert Bentham
- Henning Walczak
- Karl S. Peggs
- Yasmin Morris
- Enrique Conde-Gallastegi
Institutions
- Cancer Research UK (GB)
- London Cancer (GB)
- Recombinant Antibody Technology (United Kingdom) (GB)
- MRC Centre for Regenerative Medicine (GB)
- Fundación Ciencia and Vida (CL)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- Immune Regulation (United Kingdom) (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- IRCCS Humanitas Research Hospital (IT)
- University College London (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Immunity
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1016/j.immuni.2025.03.021
- Citations
- 17
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 13.56