Regulatory T cell depletion promotes myeloid cell activation and glioblastoma response to anti-PD1 and tumor-targeting antibodies.

Galvez-Cancino F., Navarrete M., Beattie G., Puccio S., Conde-Gallastegi E., Foster K., Morris Y., Sahwangarrom T., Karagianni D., Liu J., Lee AJX., Garyfallos DA., Simpson AP., Mastrokalos G-T., Nannini F., Costoya C., Anantharam V., Cianciotti BC., Bradley L., Garcia-Diaz C., Clements M., Shroff A., Vahid Dastjerdi F., Rota EM., Sheraz S., Bentham R., Uddin I., Walczak H., Lladser A., Reading JL., Chester KA., Pule MA., Brennan PM., Marguerat S., Parrinello S., Peggs KS., McGranahan N., Lugli E., Litchfield K., Pollard SM., Quezada SA.

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-/-Pten-/-EGFRvIII+ glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25NIB) antibody depleted Treg cells and promoted CD8+ 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-CD25NIB with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25NIB treatment of glioblastoma patient-derived tumor fragments effectively depleted Treg cells and activated CD8+ T cells. These findings underscore the therapeutic relevance of Treg targeting in glioblastoma and unveil potent combination strategies for anti-CD25NIB based on innate cell activation.

DOI

10.1016/j.immuni.2025.03.021

Type

Journal article

Publication Date

2025-05-01T00:00:00+00:00

Volume

58

Pages

1236 - 1253.e8

Addresses

Immune Regulation and Tumour Immunotherapy Laboratory, Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, UK; Immune Regulation Laboratory, Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. Electronic address: felipe.galvez-cancino@immonc.ox.ac.uk.

Keywords

CD8-Positive T-Lymphocytes, Cell Line, Tumor, Myeloid Cells, Animals, Mice, Knockout, Humans, Mice, Glioblastoma, Brain Neoplasms, Receptors, IgG, Antibodies, Monoclonal, Immunotherapy, Lymphocyte Depletion, Lymphocyte Activation, T-Lymphocytes, Regulatory, Interleukin-2 Receptor alpha Subunit, Tumor Microenvironment, Programmed Cell Death 1 Receptor, ErbB Receptors, Immune Checkpoint Inhibitors

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