Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma

• Published in: Cancers Vol. 15; no. 19; p. 4703
• Main Authors: Woo, Jong Kyu, Kim, Tae-Geuk, Im, Na Yeon, Son, Ka-Yeon, Cho, Minhyeon, Jeong, Yeo Jin, Hong, Jeong-Im, Kang, BoRim, Enkhtaivan, Gansukh, Cho, Nam-Hyuk, Alain, Tommy, Park, Dong Guk, Lee, Yeon-Sook
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.09.2023; MDPI
• Subjects: Antibodies; Antigens; Armed-Myxoma virus; Cancer; Cancer therapies; Care and treatment; CD4 antigen; CD47; CD8 antigen; Cell death; Experiments; Foxp3 protein; Foxp3+ CD4+ regulatory T-cell (T-reg); Gene expression; Health aspects; IFN-γ; Immune response; Immunotherapy; Laboratory animals; Lymphocytes; Lymphocytes T; Melanoma; Metastases; Myxoma; Oncology, Experimental; Oncolysis; oncolytic virus; PD-L1 protein; Sucrose; T cells; Transgenes; Tumor cells; Tumor suppression; Tumor-infiltrating lymphocytes; tumor-infiltrating lymphocytes (TIL); Tumors; Viral antibodies; Viruses; γ-Interferon; South Korea; United Kingdom > UK; United States > US; IFN-γ; tumor-infiltrating lymphocytes (TIL); oncolytic virus; Armed-Myxoma virus; melanoma; CD47; Foxp3+ CD4+ regulatory T-cell (T-reg)
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers15194703

Myxoma virus (MyxV) is a rabbit-specific poxvirus. However, its ability to selectively target tumor cells has established it as a safe and effective anticancer therapy. To strengthen its preclinical efficacy, transgenes that can prolong cancer cell infection and enhance anti-tumor effector functions are currently being investigated. We engineered MyxV armed with CD47, to turn on a 'do not eat me' signal within infected cells with actively replicating viruses, and with IFN-γ to further activate host immune anticancer responses. Tumor suppressive activities were significantly enhanced by the dual-armed MyxV_CD47/IFN-γ compared to parental MyxV or single-armed MyxV_CD47 or MyxV_IFN-γ. In addition, significant increases in IFN-γ+ CD8+T-cells and CD4+ T-cells populations within tumor-infiltrating lymphocytes (TIL) were observed after MyxV_CD47/IFN-γ treatment. Notably, all groups treated with MyxV showed a marked reduction in Foxp3+ CD4+ regulatory T-cells (Tregs) within TIL. We also show that MyxV infection induces PD-L1 up-regulation in cancer cells, and combinational treatment of MyxV with anti-mouse PD-L1 antibodies (αPD-L1) further controlled tumor burden and increased survival in the syngeneic melanoma model B16F10. Our data demonstrate that a CD47 and IFNγ dual-armed MyxV is an effective oncolytic viral immunotherapeutic. These findings strongly support further preclinical investigations to develop next-generation MyxV-based immunotherapy approaches.