免疫疗法对恶性胶质母细胞瘤的疗效有限，这凸显出对中枢神经系统免疫的更好理解的迫切性。我们发现，αCTLA-4的治疗延长了类骨样胶质母细胞瘤小鼠模型的生存时间，而αPD-1则没有这种效果。这种效果在CD4+ T 细胞耗尽之后丧失，但CD8+ T 细胞不受影响。αCTLA-4治疗增加了肿瘤内IFNγ产生的CD4+ T 细胞频率，并且IFNg阻断消除了αCTLA-4的治疗影响。CD4+ T 细胞的抗肿瘤活性不需要肿瘤本身的MHC-II表达，而是需要传统树突状细胞以及微胶质细胞上的MHC-II表达。CD4+ T 细胞直接与微胶质细胞作用，促进依赖IFNγ的微胶质细胞激活和吞噬作用，通过AXL/MER酪氨酸激酶受体实现，这对肿瘤抑制至关重要。因此，阿尔法CTLA-4阻断在类骨样胶质母细胞瘤中促进了CD4+ T 细胞-微胶质细胞的信号循环，在该循环中，IFNγ触发了微胶质细胞的激活和吞噬作用，而微胶质细胞则充当抗原呈递细胞，推动CD4+ T 细胞应答。版权所有© 2023 Elsevier Inc. 保留所有权利。

The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNg blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.Copyright © 2023 Elsevier Inc. All rights reserved.