Galvez-Cancino Felipe, Navarrete Mariela, Beattie Gordon, Puccio Simone, Conde-Gallastegi Enrique, Foster Kane, Morris Yasmin, Sahwangarrom Teerapon, Karagianni Despoina, Liu Jiali, Lee Alvin J X, Garyfallos Dimitrios A, Simpson Alexander P, Mastrokalos Gerasimos-Theodoros, Nannini Francesco, Costoya Cristobal, Anantharam Varshaa, Cianciotti Beatrice Claudia, Bradley Leanne, Garcia-Diaz Claudia, Clements Melanie, Shroff Aditya, Vahid Dastjerdi Fatemeh, Rota Enrique Miranda, Sheraz Shahida, Bentham Robert, Uddin Imran, Walczak Henning, Lladser Alvaro, Reading James L, Chester Kerry A, Pule Martin A, Brennan Paul M, Marguerat Samuel, Parrinello Simona, Peggs Karl S, McGranahan Nicholas, Lugli Enrico, Litchfield Kevin, Pollard Steven M, Quezada Sergio A
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.
Immune Regulation and Tumour Immunotherapy Laboratory, Cancer Immunology Unit, Research Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Immunity. 2025 May 13;58(5):1236-1253.e8. doi: 10.1016/j.immuni.2025.03.021. Epub 2025 Apr 24.
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 Nf1PtenEGFRvIII glioblastoma-bearing mice, a single dose of non-interleukin-2 (IL-2) blocking (NIB) anti-CD25 (anti-CD25) 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 with anti-EGFRvIII tumor-targeting antibodies resulted in complete tumor control. Anti-human CD25 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 based on innate cell activation.
胶质母细胞瘤总是致命的，对免疫检查点阻断反应不佳。在这里，我们研究了调节性T（Treg）细胞耗竭对胶质母细胞瘤进展和免疫治疗反应性的影响。在人类胶质母细胞瘤中，Treg细胞特征升高与较差的生存结果相关，这些细胞表达高水平的CD25。在携带Nf1PtenEGFRvIII胶质母细胞瘤的小鼠中，单剂量的非白细胞介素-2（IL-2）阻断（NIB）抗CD25（抗CD25）抗体耗竭了Treg细胞，并促进了CD8 T细胞克隆扩增和部分肿瘤控制，程序性细胞死亡-1（PD1）阻断进一步增强了这种效果。Treg细胞耗竭诱导了干扰素-γ（IFN-γ）依赖性肿瘤微环境重塑，增加了肿瘤内髓样细胞上Fcγ受体（FcγR）的表达并增强了吞噬作用。抗CD25与抗EGFRvIII肿瘤靶向抗体联合使用导致肿瘤完全得到控制。用抗人CD25治疗胶质母细胞瘤患者来源的肿瘤片段有效地耗竭了Treg细胞并激活了CD8 T细胞。这些发现强调了靶向Treg在胶质母细胞瘤治疗中的相关性，并揭示了基于先天细胞激活的抗CD25有效联合策略。
