Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA, USA.
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute (DFCI) and Harvard Medical School, Boston, MA, USA.
Nat Commun. 2021 May 11;12(1):2582. doi: 10.1038/s41467-021-22885-8.
Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.
免疫检查点抑制剂（ICBs）在所有 III 期胶质母细胞瘤（GBM）试验中均失败。在这里，我们表明调节性 T（Treg）细胞在实验性胶质细胞瘤中对 ICB 抵抗 GBM 中起关键作用。使用激动性抗体（αGITR）靶向 Treg 细胞中的糖皮质激素诱导的 TNFR 相关受体（GITR）促进 CD4 Treg 细胞分化为 CD4 效应 T 细胞，减轻 Treg 细胞介导的对肿瘤免疫反应的抑制，并在 GBM 中诱导有效的抗肿瘤效应细胞。重编程的 GBM 浸润性 Treg 细胞表达与 Th1 反应特征相关的基因，产生 IFNγ，并获得针对 GBM 肿瘤细胞的细胞毒性活性，同时失去其抑制功能。αGITR 和 αPD1 抗体增加了三种实验性 GBM 模型的生存获益，其中一部分队列在肿瘤再次挑战时表现出完全的肿瘤消除和免疫记忆。此外，αGITR 和 αPD1 与新诊断的 GBM 的标准治疗协同作用，提高了这些 GBM 模型的治愈率。
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