Yang and Giehl et al. created an oncolytic vaccinia virus (OV) expressing IL-36γ (induces IL-1), but not SPI-2 (an OV inhibitor of IL-1β-converting enzyme). IL-36γ-OV infectivity and oncolytic activities were retained, and IL-36γ was secreted by IL-36γ-OV-infected cancer cells in vitro. In mice, OVs replicated for a few days and high IL-36γ levels persisted in infected tumor tissues six days after injection. IL-36γ-OV treatment of murine syngeneic tumor models reduced intratumoral (IT) M2-like macrophages and myeloid-derived suppressor cells, increased IT NK cells, DCs, and tumor- and virus-specific CD8+ and CD4+ T cells, and mediated primary and recall antitumor responses.
Contributed by Paula Hochman
ABSTRACT: In this study, we aimed to apply the cytokine IL-36γ to cancer immunotherapy by constructing new oncolytic vaccinia viruses (OV) expressing interleukin-36γ (IL-36γ-OVs), leveraging unique synergism between OV and IL-36γ's ability to promote antitumor adaptive immunity and modulate tumor microenvironment (TME). IL-36γ-OV had dramatic therapeutic efficacies in multiple murine tumor models, frequently leading to complete cancer eradication in large fractions of mice. Mechanistically, IL-36-γ-armed OV induced infiltration of lymphocytes and dendritic cells, decreased myeloid-derived suppressor cells and M2-like tumor-associated macrophages, and T cell differentiation into effector cells. Further study showed that IL-36γ-OV increased the number of tumor antigen-specific CD4+ and CD8+ T cells and the therapeutic efficacy depended on both CD8+ and CD4+ T cells. These results demonstrate that these IL36γ-armed OVs exert potent therapeutic efficacy mainly though antitumor immunity and they may hold great potential to advance treatment in human cancer patients.