Grimes Jeffrey M, Ghosh Sadashib, Manzoor Shamza, Li Li X, Moran Monica M, Clements Jennifer C, Alexander Sherrie D, Markert James M, Leavenworth Jianmei W
Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA.
Nat Commun. 2025 Jan 30;16(1):1095. doi: 10.1038/s41467-024-55455-9.
Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4 T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12. The upregulated MHCII on residual tumor cells facilitates programmed polyfunctional CD4 T cells for tumor control and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4 T cells navigates their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4 T-cell subset, which requires MHCII signals from reprogrammed tumor cells, tumor-infiltrating and resident myeloid cells, is necessary for the prolonged response. These findings uncover an OV-induced tumor/myeloid-CD4 T-cell partnership, leading to long-term anti-tumor immune memory, and improved OV therapeutic efficacy.
溶瘤病毒（OVs）作为一种很有前景的癌症免疫疗法出现。然而，其对肿瘤细胞和肿瘤微环境的时间影响，以及治疗后抗肿瘤免疫的性质在很大程度上仍不清楚。在此，我们报告在用工程改造后表达白细胞介素-12的溶瘤单纯疱疹病毒（oHSV）治疗多形性胶质母细胞瘤的同基因小鼠模型中，持久控制肿瘤需要CD4 T细胞。残留肿瘤细胞上上调的主要组织相容性复合体II类分子（MHCII）促进了用于肿瘤控制和回忆反应的程序化多功能CD4 T细胞。从机制上讲，CD4 T细胞中Bcl-6与T-bet的适当比例引导其增强的抗肿瘤能力，并且记忆CD4 T细胞亚群中的相互白细胞介素6受体α（IL6ra）-Bcl-6调节轴对于延长反应是必要的，该轴需要来自重编程肿瘤细胞、肿瘤浸润和驻留髓系细胞的MHCII信号。这些发现揭示了一种OV诱导的肿瘤/髓系-CD4 T细胞伙伴关系，导致长期抗肿瘤免疫记忆，并提高了OV治疗效果。
