Reovirus virotherapy overrides tumor antigen presentation evasion and promotes protective antitumor immunity.
Tumor-associated immunosuppressive strategies, such as lack of tumor antigen recognition and failure of lymphocyte activation and homing, resist the development of tumor-specific immunity and hamper the immune response-mediated elimination of cancerous cells. In this report, we show that reovirus virotherapy overrides such a tumor immune evasion and establishes clinically meaningful antitumor immunity capable of protecting against subsequent tumor challenge. Reovirus-mediated destruction of tumor cells facilitates the recognition of tumor antigens by promoting the display of otherwise inaccessible tumor-specific immunogenic peptides on the surface of dendritic cells (DC). Furthermore, on exposure to reovirus, DCs produce IL-1α, IL-1β, IL-6, IL-12p40/70, IL-17, CD30L, eotaxin, GM-CSF, KC, MCP-1, MCP-5, M-CSF, MIG, MIP-1α, RANTES, TNF-α, VCAM-1, VSGF, CXCL-16, AXL, and MCP-2; undergo maturation; and migrate into the tumor microenvironment along with CD8 T cells. These reovirus-activated DCs also acquire the capacity to prime tumor antigen-specific transgenic T cells in vitro and intrinsic antitumor T-cell response in vivo. Further, reovirus virotherapy augments the efficacy of DC- or T cell-based anticancer immunotherapies and synergistically enhances the survival in tumor-bearing mice. Most importantly, antitumor cellular immune responses initiated during reovirus oncotherapy protect the host against subsequent tumor challenge in a reovirus-independent but antigen-dependent manner. These reovirus oncotherapy-initiated antitumor immune responses represent an anticancer therapeutic entity that can maintain a long-term cancer-free health even after discontinuation of therapy.
Department of Pathology and Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Room 7-P, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, Nova Scotia, Canada B3H 1X5.
Shashi A
SA
Gujar
Paola
P
Marcato
Da
D
Pan
Patrick W K
PW
Lee
D056704:Adaptive Immunity / Q000502:physiology; D000818:Animals; D017951:Antigen Presentation / Q000502:physiology; D000951:Antigens, Neoplasm / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation / Q000821:virology; D005260:Female; D056747:Immunomodulation / Q000502:physiology; D012089:Mammalian orthoreovirus 3 / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D050130:Oncolytic Virotherapy; D019139:Tumor Escape / Q000276:immunology*
D000951:Antigens, Neoplasm