Grimes et al. interrogated an IL-12 oncolytic virus (M002) in glioblastoma in mice. CD4+ T cells were required for efficacy, and M002 significantly increased infiltration and polyfunctionality while specifically expanding a Bcl-6+ memory-like cluster. M002 upregulated MHC-II on tumor cells, blockade of which abrogated the superior tumor cell killing by treated CD4+ cells. M002 was associated with an early elevation of T-bet and late induction of Bcl-6 in CD4+ cells, and late Bcl-6 knockdown blunted efficacy in treated mice. Lineage analysis revealed co-regulation of IL-6ra and Bcl-6 in the memory subset, which was confirmed by scRNAseq and in vitro killing experiments.
Contributed by Morgan Janes
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.
Author Info: (1) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL,
Author Info: (1) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA. (2) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (3) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (4) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (5) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. Graduate Biomedical Sciences Program, University of Alabama at Birmingham, Birmingham, AL, USA. (6) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (7) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. (8) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. The O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. (9) Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL, USA. jleavenworth@uabmc.edu. The O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. jleavenworth@uabmc.edu. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA. jleavenworth@uabmc.edu.
