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.
Author Info: (1) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (2) UPMC Hillman Cancer Center, Pit
Author Info: (1) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (2) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, 01307, Dresden, Germany. (3) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (4) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Department of Surgery, CCM/CVK, Charit-Universitaetsmedizin Berlin, Berlin, Germany. (5) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (6) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (7) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (8) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (9) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. (10) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. AHN-Cancer Institute, Pittsburgh, PA, USA. (11) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. binfeng@pitt.edu. Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. binfeng@pitt.edu. (12) UPMC Hillman Cancer Center, Pittsburgh, PA, USA. guozs@upmc.edu. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. guozs@upmc.edu.
