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- W4313405735 abstract "Abstract Although some work has been done to understand the equilibrium phase of cancer immunoediting, it is still common for immunotherapies to generate stable disease or for patients to relapse after being seemingly tumor-free. We have repurposed the non-lytic herpes simplex virus (HSV)-1 d106S vaccine vector for local delivery of IL-12. Our replication-defective d106S virus releases a large burst of IL-12 locally within the tumor environment, synergizing with a type I IFN response induced by the virus. We have shown that d106S-IL12 induces regression and long-term stable immune equilibrium in murine B16 melanoma. Intriguingly, individual depletion of CD8+ T cells, CD4+ T cells, or NK cells does not affect stable tumor control. However, triple depletion of these cell types leads to tumor outgrowth suggesting these cells have redundant functions. Indeed, IFNγ, likely secreted by these lymphocytes, is essential for controlling tumors in response to d106S-IL12 treatment. The inability of tumors to respond to IFNγ and present antigen to CD8+ T cells through MHC-I often renders tumors resistant to checkpoint blockade and other immunotherapies reliant on direct T cell cytotoxicity. Surprisingly, B16 tumors defective in IFNγ-sensing or MHC-I presentation are still stably maintained in response to IL-12 virotherapy. This suggests that while IFNγ secretion by lymphocytes is necessary, IFNγ and the lymphocytes themselves are not required to act directly on cancer cells to stably control tumor growth. Single-cell RNA-sequencing of immune cells infiltrating the tumor indicates that IFNγ is primarily acting on myeloid cells. Thus, myeloid cells activated by IFNγ may be a method to control growth of checkpoint blockade-resistant tumors. Supported by grants from NIH (P01-AI098681) and Melanoma Research Alliance" @default.
- W4313405735 created "2023-01-06" @default.
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- W4313405735 date "2022-05-01" @default.
- W4313405735 modified "2023-09-26" @default.
- W4313405735 title "IFNγ from IL-12 virotherapy stably controls tumors independent of T cell cytotoxicity and IFNγ sensing by tumor cells" @default.
- W4313405735 doi "https://doi.org/10.4049/jimmunol.208.supp.118.07" @default.
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