Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma
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...
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MDPI AG
2023-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/19/4703 |
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| author | Jong Kyu Woo Tae-Geuk Kim Na Yeon Im Ka-Yeon Son Minhyeon Cho Yeo Jin Jeong Jeong-Im Hong BoRim Kang Gansukh Enkhtaivan Nam-Hyuk Cho Tommy Alain Dong Guk Park Yeon-Sook Lee |
| author_facet | Jong Kyu Woo Tae-Geuk Kim Na Yeon Im Ka-Yeon Son Minhyeon Cho Yeo Jin Jeong Jeong-Im Hong BoRim Kang Gansukh Enkhtaivan Nam-Hyuk Cho Tommy Alain Dong Guk Park Yeon-Sook Lee |
| author_sort | Jong Kyu Woo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T21:48:21Z |
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| id | doaj.art-26010cea9e2a4febafbd6f8211f6f5c3 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T21:48:21Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-26010cea9e2a4febafbd6f8211f6f5c32023-11-19T14:09:22ZengMDPI AGCancers2072-66942023-09-011519470310.3390/cancers15194703Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine MelanomaJong Kyu Woo0Tae-Geuk Kim1Na Yeon Im2Ka-Yeon Son3Minhyeon Cho4Yeo Jin Jeong5Jeong-Im Hong6BoRim Kang7Gansukh Enkhtaivan8Nam-Hyuk Cho9Tommy Alain10Dong Guk Park11Yeon-Sook Lee12ViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaDepartment of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 08826, Republic of KoreaDepartment of Biochemistry, Microbiology and Immunology, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1N 6N5, CanadaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaViroCure, #502, Ace TwinTower 1, 285 Digital-ro, Guro-gu, Seoul 08381, Republic of KoreaMyxoma 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.https://www.mdpi.com/2072-6694/15/19/4703oncolytic virusArmed-Myxoma virusCD47IFN-γtumor-infiltrating lymphocytes (TIL)Foxp3+ CD4+ regulatory T-cell (T-reg) |
| spellingShingle | Jong Kyu Woo Tae-Geuk Kim Na Yeon Im Ka-Yeon Son Minhyeon Cho Yeo Jin Jeong Jeong-Im Hong BoRim Kang Gansukh Enkhtaivan Nam-Hyuk Cho Tommy Alain Dong Guk Park Yeon-Sook Lee Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma Cancers oncolytic virus Armed-Myxoma virus CD47 IFN-γ tumor-infiltrating lymphocytes (TIL) Foxp3+ CD4+ regulatory T-cell (T-reg) |
| title | Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma |
| title_full | Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma |
| title_fullStr | Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma |
| title_full_unstemmed | Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma |
| title_short | Dual-Armed Oncolytic Myxoma Virus Encoding IFN-γ and CD47 Promotes Lymphocyte Infiltration and Tumor Suppression of Syngeneic Murine Melanoma |
| title_sort | dual armed oncolytic myxoma virus encoding ifn γ and cd47 promotes lymphocyte infiltration and tumor suppression of syngeneic murine melanoma |
| topic | oncolytic virus Armed-Myxoma virus CD47 IFN-γ tumor-infiltrating lymphocytes (TIL) Foxp3+ CD4+ regulatory T-cell (T-reg) |
| url | https://www.mdpi.com/2072-6694/15/19/4703 |
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