Regulatory T cell depletion promotes myeloid cell activation and glioblastoma response to anti-PD1 and tumor-targeting antibodies
Felipe Gálvez‐Cancino, Mariela Navarrete, Gordon Beattie, Simone Puccio, Enrique Conde-Gallastegi, Kane Foster, Yasmin Morris, Teerapon Sahwangarrom, Despoina Karagianni, Jiali Liu, A. Lee, Dimitrios A. Garyfallos, Alexander P. Simpson, Gerasimos-Theodoros Mastrokalos, Francesco Nannini, Cristóbal Costoya, Varshaa Anantharam, Beatrice Claudia Cianciotti, Leanne Bradley, Claudia Garcia-Diaz, Melanie Clements, Aditya Shroff, Fatemeh Vahid Dastjerdi, Enrique Miranda Rota, Shahida Sheraz, Robert Bentham, Imran Uddin, Henning Walczak, Álvaro Lladser, James L. Reading, Kerry Chester, Martin Pulé, Paul M. Brennan, Samuel Marguerat, Simona Parrinello, Karl S. Peggs, Nicholas McGranahan, Enrico Lugli, Kevin Litchfield, Steven M. Pollard, Sergio A. Quezada
Abstract
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-CD25 NIB ) 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-CD25 NIB with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25 NIB 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-CD25 NIB based on innate cell activation.