胶质母细胞瘤 (GBM) 具有高度免疫抑制的肿瘤免疫微环境 (TIME)，主要由骨髓源性抑制细胞 (MDSC) 介导。在这里，我们利用逆转录病毒复制载体 (RRV) 在同基因小鼠 GBM 模型中传递干扰素调节因子 8 (IRF8)，干扰素调节因子 8 (IRF8) 是 1 型常规树突细胞 (cDC1) 发育的主要调节因子。我们假设 RRV 介导的 IRF8 递送可以将瘤内 MDSC“重编程”为抗原呈递细胞 (APC)，从而恢复 T 细胞反应。在 SB28 鼠 GBM 模型中检查了 RRV-IRF8 对生存和肿瘤生长动力学的影响。通过流式细胞术和基因表达测定来分析免疫表型。我们通过离体T细胞-骨髓共培养来测定功能性免疫抑制和抗原呈递。在患有脑内SB28神经胶质瘤的小鼠中瘤内注射RRV-IRF8可显着抑制肿瘤生长并延长生存期。 RRV-IRF8 处理的肿瘤表现出 cDC1 和 CD8 T 细胞的显着富集。此外，与对照相比，来自RRV-IRF8肿瘤的骨髓细胞显示出免疫抑制标记物Arg1和IDO1的表达降低，并且在离体共培养中表现出对幼稚T细胞增殖的抑制减少。此外，与对照肿瘤的 DC 相比，RRV-IRF8 肿瘤的 DC 表现出抗原呈递增加。使用病毒复制抑制剂叠氮胸苷 (AZT) 进行体内治疗表明，肿瘤细胞和非肿瘤细胞中的 IRF8 转导对于生存获益是必要的，与重新编程的富含 cDC1 和 CD8 T 细胞的 TIME 相关。我们的结果表明通过体内表达 IRF8 对胶质瘤浸润性骨髓细胞进行重编程可能会减少免疫抑制并增强抗原呈递，从而改善肿瘤控制。© 作者 2024。由牛津大学出版社代表神经肿瘤学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore T-cell responses.Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by ex vivo T-cell-myeloid co-culture.Intratumoral injection of RRV-IRF8 in mice bearing intracerebral SB28 glioma significantly suppressed the tumor growth and prolonged survival. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in ex vivo co-culture, compared to controls. Furthermore, DCs from RRV-IRF8 tumors showed increased antigen presentation compared to those from control tumors. In vivo treatment with azidothymidine (AZT), a viral replication inhibitor, showed that IRF8 transduction in both tumor and non-tumor cells is necessary for survival benefit, associated with a reprogrammed, cDC1- and CD8 T-cell-enriched TIME.Our results indicate that reprogramming of glioma-infiltrating myeloid cells by in vivo expression of IRF8 may reduce immunosuppression and enhance antigen presentation, achieving improved tumor control.© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.