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Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted
Jeffrey M Grimes1,2, Sadashib Ghosh1, Shamza Manzoor1
1Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA.
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.
Insights
CD4+ T cells are crucial for durable tumor control after oncolytic virus (OV) therapy for glioblastoma. This study reveals an OV-induced partnership between tumor cells, myeloid cells, and CD4+ T cells, enhancing anti-tumor immunity and memory.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- Oncolytic viruses (OVs) show promise in cancer immunotherapy.
- The long-term effects of OVs on anti-tumor immunity are not fully understood.
Purpose of the Study:
- To investigate the role of CD4+ T cells in durable tumor control following oncolytic herpes simplex virus (oHSV) therapy.
- To elucidate the mechanisms underlying OV-induced anti-tumor immunity and immune memory.
Main Methods:
- Syngeneic murine glioblastoma models treated with IL-12-expressing oHSV.
- Analysis of CD4+ T cell function, tumor cell MHCII expression, and key transcription factors (Bcl-6, T-bet).
Main Results:
- CD4+ T cells are essential for durable tumor control after oHSV therapy.
- Upregulated MHCII on tumor cells promotes polyfunctional CD4+ T cells.
- A Bcl-6/T-bet ratio and an IL6ra-Bcl-6 axis in memory CD4+ T cells are critical for sustained anti-tumor responses.
Conclusions:
- Oncolytic virus therapy establishes a tumor/myeloid-CD4+ T cell partnership.
- This partnership leads to long-term anti-tumor immune memory and improved therapeutic efficacy.
- Findings highlight the importance of CD4+ T cell-mediated immunity in OV cancer treatment.
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