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Oncolytic reprogramming of tumor microenvironment shapes the IL6ra/Bcl6-dependent CD4 T-cell memory to control glioblastoma 4494

Year: 2025
Type: article
Abstract: Description Oncolytic viruses (OVs) have emerged as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of sustained anti-tumor immunity post-therapy remain largely unclear. Here we identified CD4+ T-cells as the critical cellular component that was responsible for oncolytic herpes simplex virus (oHSV)-mediated durable control of tumor in syngeneic murine models of glioblastoma (GBM), a type of lethal brain tumor. oHSV treatment upregulated MHCII on residual tumor cells that was important for programmed polyfunctional CD4+ T-cells to control tumor and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4+ T-cells was crucial for their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4+ T-cell subset was necessary for the prolonged response. Remarkably, the reprogrammed tumor cells along with tumor-infiltrating and resident myeloid cells provided MHCII-mediated interactions to facilitate the generation of this memory population. These findings uncover an OV-induced tumor/innate immune cell-CD4+ T-cell partnership, leading to tumor rejection by CD4+ T-cells, long-term anti-tumor immune memory, and improved OV therapeutic efficacy. Funding Sources Supported by DoD W81XWH-18-1-0315, and the UAB faculty start-up funds (J.W.L.). J.W.L is also supported by NIH R01AI148711, R01AI148711-03S1/04S1 (via NIA), R01CA276190, R21CA278853, DoD HT9425-23-1-0792, American Cancer Society RSG-23-1038722-01-IBCD and Breast Cancer Research Foundation of Alabama. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
DOI: 10.1093/jimmun/vkaf283.2169
Language: English
Subfield: Genetics
Open Access status: bronze
OpenAlex ID: W4416449828
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