Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity
CD4+ T cells can induce potent anti-tumor immune responses. Due to the lack of MHC class II expression in most cancer cells, antigen recognition occurs indirectly via uptake and presentation on tumor-infiltrating antigen-presenting cells (APCs). Activation of the APCs can induce tumor rejection, but...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.01684/full |
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| author | Marte Fauskanger Ole Audun Werner Haabeth Frode Miltzow Skjeldal Frode Miltzow Skjeldal Bjarne Bogen Bjarne Bogen Anders Aune Tveita |
| author_facet | Marte Fauskanger Ole Audun Werner Haabeth Frode Miltzow Skjeldal Frode Miltzow Skjeldal Bjarne Bogen Bjarne Bogen Anders Aune Tveita |
| author_sort | Marte Fauskanger |
| collection | DOAJ |
| description | CD4+ T cells can induce potent anti-tumor immune responses. Due to the lack of MHC class II expression in most cancer cells, antigen recognition occurs indirectly via uptake and presentation on tumor-infiltrating antigen-presenting cells (APCs). Activation of the APCs can induce tumor rejection, but the mechanisms underlying tumor killing by such cells have not been established. To elucidate the molecular basis of CD4+ T-cell-mediated tumor rejection, we utilized a murine model of multiple myeloma, in which the T cells recognize a secreted tumor neoantigen. Our findings demonstrate that T cell recognition triggers inducible nitric oxide synthase activity within tumor-infiltrating macrophages. Diffusion of nitric oxide into surrounding tumor cells results in intracellular accumulation of toxic secondary oxidants, notably peroxynitrite. This results in tumor cell apoptosis through activation of the mitochondrial pathway. We find that this mode of cytotoxicity has strict spatial limitations, and is restricted to the immediate surroundings of the activated macrophage, thus limiting bystander killing. These findings provide a molecular basis for macrophage-mediated anti-tumor immune responses orchestrated by CD4+ T cells. Since macrophages are abundant in most solid tumors, evoking the secretion of nitric oxide by such cells may represent a potent therapeutic strategy. |
| first_indexed | 2024-04-12T00:01:36Z |
| format | Article |
| id | doaj.art-6c94c9839df7424f979ae08ac4b7e34d |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T00:01:36Z |
| publishDate | 2018-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-6c94c9839df7424f979ae08ac4b7e34d2022-12-22T03:56:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-07-01910.3389/fimmu.2018.01684388824Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage CytotoxicityMarte Fauskanger0Ole Audun Werner Haabeth1Frode Miltzow Skjeldal2Frode Miltzow Skjeldal3Bjarne Bogen4Bjarne Bogen5Anders Aune Tveita6Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, NorwayDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, NorwayDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, NorwayDepartment of Biosciences, University of Oslo, Oslo, NorwayDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, NorwayKG Jebsen Centre for Influenza Vaccine Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, NorwayDepartment of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, NorwayCD4+ T cells can induce potent anti-tumor immune responses. Due to the lack of MHC class II expression in most cancer cells, antigen recognition occurs indirectly via uptake and presentation on tumor-infiltrating antigen-presenting cells (APCs). Activation of the APCs can induce tumor rejection, but the mechanisms underlying tumor killing by such cells have not been established. To elucidate the molecular basis of CD4+ T-cell-mediated tumor rejection, we utilized a murine model of multiple myeloma, in which the T cells recognize a secreted tumor neoantigen. Our findings demonstrate that T cell recognition triggers inducible nitric oxide synthase activity within tumor-infiltrating macrophages. Diffusion of nitric oxide into surrounding tumor cells results in intracellular accumulation of toxic secondary oxidants, notably peroxynitrite. This results in tumor cell apoptosis through activation of the mitochondrial pathway. We find that this mode of cytotoxicity has strict spatial limitations, and is restricted to the immediate surroundings of the activated macrophage, thus limiting bystander killing. These findings provide a molecular basis for macrophage-mediated anti-tumor immune responses orchestrated by CD4+ T cells. Since macrophages are abundant in most solid tumors, evoking the secretion of nitric oxide by such cells may represent a potent therapeutic strategy.https://www.frontiersin.org/article/10.3389/fimmu.2018.01684/fullmacrophageCD4+ T cellimmunotherapymyelomanitric oxide |
| spellingShingle | Marte Fauskanger Ole Audun Werner Haabeth Frode Miltzow Skjeldal Frode Miltzow Skjeldal Bjarne Bogen Bjarne Bogen Anders Aune Tveita Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity Frontiers in Immunology macrophage CD4+ T cell immunotherapy myeloma nitric oxide |
| title | Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity |
| title_full | Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity |
| title_fullStr | Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity |
| title_full_unstemmed | Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity |
| title_short | Tumor Killing by CD4+ T Cells Is Mediated via Induction of Inducible Nitric Oxide Synthase-Dependent Macrophage Cytotoxicity |
| title_sort | tumor killing by cd4 t cells is mediated via induction of inducible nitric oxide synthase dependent macrophage cytotoxicity |
| topic | macrophage CD4+ T cell immunotherapy myeloma nitric oxide |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.01684/full |
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