2025年4月24日，伦敦大学学院Sergio A. Quezada研究小组在《免疫学》杂志发表论文，报道了调节性T细胞耗竭促进髓细胞活化和胶质母细胞瘤对抗PD1和肿瘤靶向抗体的反应。

研究组研究了调节性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，升高的Treg细胞特征与较差的生存结果相关，这些细胞表达高水平的CD25。在携带Nf1^-/-Pten^-/-EGFRvIII⁺胶质母细胞瘤的小鼠中，单剂量非白细胞介素-2（IL-2）阻断（NIB）抗CD25（抗CD25^NIB）抗体耗尽Treg细胞，促进CD8⁺T细胞克隆扩增和部分肿瘤控制，并通过程序性细胞死亡-1（PD1）阻断进一步增强。Treg细胞耗竭诱导干扰素-γ (IFN-γ)依赖的肿瘤微环境重塑，增加肿瘤内骨髓细胞中Fcγ受体（Fcγ r）的表达，增强吞噬作用。抗CD25^NIB与抗EGFRvIII肿瘤靶向抗体的联合使用可完全控制肿瘤。抗人CD25^NIB治疗胶质母细胞瘤患者来源的肿瘤碎片有效地耗尽Treg细胞并激活CD8⁺ T细胞。这些发现强调了Treg靶向胶质母细胞瘤的治疗相关性，并揭示了基于先天细胞激活的抗CD25^NIB的有效联合策略。

据介绍，胶质母细胞瘤总是致命的，对免疫检查点封锁反应不佳。

附：英文原文

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

Author: Felipe Galvez-Cancino, Mariela Navarrete, Gordon Beattie, Simone Puccio, Enrique Conde-Gallastegi, Kane Foster, Yasmin Morris, Teerapon Sahwangarrom, Despoina Karagianni, Jiali Liu, Alvin J.X. lee, Dimitrios A. Garyfallos, Alexander P. Simpson, Gerasimos-Theodoros Mastrokalos, Francesco Nannini, Cristobal 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, Alvaro Lladser, James L. Reading, Kerry A. Chester, Martin A. Pule, Paul M. Brennan, Samuel Marguerat, Simona Parrinello, Karl S. Peggs, Nicholas McGranahan, Enrico Lugli, Kevin Litchfield, Steven M. Pollard, Sergio A. Quezada

Issue&Volume: 2025-04-24

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-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

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00162-1