Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer
IntroductionTumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associa...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1325558/full |
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| author | Lisa A. Santry Jacob P. van Vloten Amanda W. K. AuYeung Robert C. Mould Jacob G. E. Yates Thomas M. McAusland James J. Petrik Pierre P. Major Byram W. Bridle Sarah K. Wootton |
| author_facet | Lisa A. Santry Jacob P. van Vloten Amanda W. K. AuYeung Robert C. Mould Jacob G. E. Yates Thomas M. McAusland James J. Petrik Pierre P. Major Byram W. Bridle Sarah K. Wootton |
| author_sort | Lisa A. Santry |
| collection | DOAJ |
| description | IntroductionTumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs).MethodsTo reverse this immunosuppression, we engineered mesogenic Newcastle disease virus (NDV) to express immunological checkpoint inhibitors anti-cytotoxic T lymphocyte antigen-4 and soluble programmed death protein-1.ResultsIntratumoral administration of recombinant NDV (rNDV) to mice bearing intradermal B16-F10 melanomas or subcutaneous CT26LacZ colon carcinomas led to significant changes in the tumor-infiltrating lymphocyte profiles. Vectorizing immunological checkpoint inhibitors in NDV increased activation of intratumoral natural killer cells and cytotoxic T cells and decreased Tregs and MDSCs, suggesting induction of a pro-inflammatory state with greater infiltration of activated CD8+ T cells. These notable changes translated to higher ratios of activated effector/suppressor tumor-infiltrating lymphocytes in both cancer models, which is a promising prognostic marker. Whereas all rNDV-treated groups showed evidence of tumor regression and increased survival in the CT26LacZ and B16-F10, only treatment with NDV expressing immunological checkpoint blockades led to complete responses compared to tumors treated with NDV only.DiscussionThese data demonstrated that NDV expressing immunological checkpoint inhibitors could reverse the immunosuppressive state of tumor microenvironments and enhance tumor-specific T cell responses. |
| first_indexed | 2024-03-08T11:54:01Z |
| format | Article |
| id | doaj.art-0dc2b238fb124dce87ad725117251258 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-03-08T11:54:01Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-0dc2b238fb124dce87ad7251172512582024-01-24T04:49:10ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2024-01-011510.3389/fmicb.2024.13255581325558Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancerLisa A. Santry0Jacob P. van Vloten1Amanda W. K. AuYeung2Robert C. Mould3Jacob G. E. Yates4Thomas M. McAusland5James J. Petrik6Pierre P. Major7Byram W. Bridle8Sarah K. Wootton9Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaJuravinski Cancer Center, Hamilton, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaDepartment of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON, CanadaIntroductionTumor microenvironments are immunosuppressive due to progressive accumulation of mutations in cancer cells that can drive expression of a range of inhibitory ligands and cytokines, and recruitment of immunomodulatory cells, including myeloid-derived suppressor cells (MDSC), tumor-associated macrophages, and regulatory T cells (Tregs).MethodsTo reverse this immunosuppression, we engineered mesogenic Newcastle disease virus (NDV) to express immunological checkpoint inhibitors anti-cytotoxic T lymphocyte antigen-4 and soluble programmed death protein-1.ResultsIntratumoral administration of recombinant NDV (rNDV) to mice bearing intradermal B16-F10 melanomas or subcutaneous CT26LacZ colon carcinomas led to significant changes in the tumor-infiltrating lymphocyte profiles. Vectorizing immunological checkpoint inhibitors in NDV increased activation of intratumoral natural killer cells and cytotoxic T cells and decreased Tregs and MDSCs, suggesting induction of a pro-inflammatory state with greater infiltration of activated CD8+ T cells. These notable changes translated to higher ratios of activated effector/suppressor tumor-infiltrating lymphocytes in both cancer models, which is a promising prognostic marker. Whereas all rNDV-treated groups showed evidence of tumor regression and increased survival in the CT26LacZ and B16-F10, only treatment with NDV expressing immunological checkpoint blockades led to complete responses compared to tumors treated with NDV only.DiscussionThese data demonstrated that NDV expressing immunological checkpoint inhibitors could reverse the immunosuppressive state of tumor microenvironments and enhance tumor-specific T cell responses.https://www.frontiersin.org/articles/10.3389/fmicb.2024.1325558/fullNewcastle disease virus (NDV)oncolytic virusimmunological checkpoint inhibitorsanti-CTLA-4PD-1PD-L1 |
| spellingShingle | Lisa A. Santry Jacob P. van Vloten Amanda W. K. AuYeung Robert C. Mould Jacob G. E. Yates Thomas M. McAusland James J. Petrik Pierre P. Major Byram W. Bridle Sarah K. Wootton Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer Frontiers in Microbiology Newcastle disease virus (NDV) oncolytic virus immunological checkpoint inhibitors anti-CTLA-4 PD-1 PD-L1 |
| title | Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer |
| title_full | Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer |
| title_fullStr | Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer |
| title_full_unstemmed | Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer |
| title_short | Recombinant Newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro-inflammatory state and enhance tumor-specific immune responses in two murine models of cancer |
| title_sort | recombinant newcastle disease viruses expressing immunological checkpoint inhibitors induce a pro inflammatory state and enhance tumor specific immune responses in two murine models of cancer |
| topic | Newcastle disease virus (NDV) oncolytic virus immunological checkpoint inhibitors anti-CTLA-4 PD-1 PD-L1 |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1325558/full |
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