美国索尔克生物研究所Susan M. Kaech小组的研究表明，CTLA-4阻断通过诱导产生IFNγ的CD4⁺ T细胞导致胶质母细胞瘤小胶质细胞吞噬作用和抗肿瘤功能。该研究于2023年8月11日发表于国际学术期刊《免疫》杂志上。

研究人员发现，用αCTLA-4而不是αPD-1治疗延长了间充质样胶质母细胞瘤小鼠模型的生存期。这种效应在CD4⁺ T细胞而非CD8⁺ T耗竭时消失。αCTLA-4治疗增加了产生IFNγ的CD4⁺ T细胞在肿瘤内的出现频率，IFNg阻断抵消了αCTLA-4的治疗效果。CD4⁺ T细胞的抗肿瘤活性不需要肿瘤内MHC-II的表达，而是需要常规树突状细胞以及小胶质细胞中表达的MHC-II。CD4⁺ T细胞直接与小胶质细胞相互作用，通过AXL/MER酪氨酸激酶受体促进IFNγ依赖性小胶质细胞活化和吞噬作用，这是抑制肿瘤所必需的。

因此，在间充质样胶质母细胞瘤中阻断αCTLA-4会促进CD4⁺ T细胞-小胶质细胞回路，其中IFNγ会触发小胶质细胞活化和吞噬作用，小胶质细胞反过来充当抗原呈递细胞，促进CD4⁺ T细胞反应。

据了解，免疫疗法对胶质母细胞瘤的有限疗效突出了更好地了解中枢神经系统免疫力的紧迫性。

附：英文原文

Title: CTLA-4 blockade induces CD4+ T cell IFNγ-driven microglial phagocytosis and anti-tumor function in glioblastoma

Author: Dan Chen, Siva Karthik Varanasi, Toshiro Hara, Kacie Traina, Ming Sun, Bryan McDonald, Yagmur Farsakoglu, Josh Clanton, Shihao Xu, Lizmarie Garcia-Rivera, Thomas H. Mann, Victor Du, H. Kay Chung, Ziyan Xu, Victoria Tripple, Eduardo Casillas, Shixin Ma, Carolyn O’Connor, Qiyuan Yang, Ye Zheng, Tony Hunter, Greg Lemke, Susan M. Kaech

Issue&Volume: 2023-08-11

Abstract: The limited efficacy of immunotherapies against glioblastoma underscores the urgencyof better understanding immunity in the central nervous system. We found that treatmentwith αCTLA-4, but not αPD-1, prolonged survival in a mouse model of mesenchymal-likeglioblastoma. 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-tumoractivity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventionaldendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activationand phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumorsuppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosisand microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.

DOI: 10.1016/j.immuni.2023.07.015

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00328-X