Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma

Jeffrey M. Grimes, Sadashib Ghosh, Shamza Manzoor, Li X. Li, Monica M. Moran, Jennifer C. Clements, Sherrie D. Alexander, James M. Markert and Jianmei W. Leavenworth ()
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Jeffrey M. Grimes: University of Alabama at Birmingham
Sadashib Ghosh: University of Alabama at Birmingham
Shamza Manzoor: University of Alabama at Birmingham
Li X. Li: University of Alabama at Birmingham
Monica M. Moran: University of Alabama at Birmingham
Jennifer C. Clements: University of Alabama at Birmingham
Sherrie D. Alexander: University of Alabama at Birmingham
James M. Markert: University of Alabama at Birmingham
Jianmei W. Leavenworth: University of Alabama at Birmingham

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-024-55455-9

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