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Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors
Treatment of solid tumors is often hindered by an immunosuppressive tumor microenvironment (TME) that prevents effector immune cells from eradicating tumor cells and promotes tumor progression, angiogenesis, and metastasis. Therefore, targeting components of the TME to restore the ability of immune...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359428/ https://www.ncbi.nlm.nih.gov/pubmed/33205451 http://dx.doi.org/10.1002/JLB.3A0520-333R |
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author | Hijaze, Nizar Ledersnaider, Max Simanovich, Elina Kassem, Sameer Rahat, Michal A. |
author_facet | Hijaze, Nizar Ledersnaider, Max Simanovich, Elina Kassem, Sameer Rahat, Michal A. |
author_sort | Hijaze, Nizar |
collection | PubMed |
description | Treatment of solid tumors is often hindered by an immunosuppressive tumor microenvironment (TME) that prevents effector immune cells from eradicating tumor cells and promotes tumor progression, angiogenesis, and metastasis. Therefore, targeting components of the TME to restore the ability of immune cells to drive anti‐tumoral responses has become an important goal. One option is to induce an immunogenic cell death (ICD) of tumor cells that would trigger an adaptive anti‐tumoral immune response. Here we show that incubating mouse renal cell carcinoma (RENCA) and colon carcinoma cell lines with an anti‐extracellular matrix metalloproteinase inducer polyclonal antibody (161‐pAb) together with complement factors can induce cell death that inhibits caspase‐8 activity and enhances the phosphorylation of receptor‐interacting protein kinase 3 (RIPK3) and mixed‐lineage kinase‐like domain (MLKL). This regulated necrotic death releases high levels of dsRNA molecules to the conditioned medium (CM) relative to the necrotic death of tumor cells induced by H(2)O(2) or the apoptotic death induced by etoposide. RAW 264.7 macrophages incubated with the CM derived from these dying cells markedly enhanced the secretion of IFNβ, and enhanced their cytotoxicity. Furthermore, degradation of the dsRNA in the CM abolished the ability of RAW 264.7 macrophages to secrete IFNβ, IFNγ‐induced protein 10 (IP‐10), and TRAIL. When mice bearing RENCA tumors were immunized with the 161‐pAb, their lysates displayed elevated levels of phosphorylated RIPK3 and MLKL, as well as increased concentrations of dsRNA, IFNβ, IP‐10, and TRAIL. This shows that an antigen‐targeted therapy using an antibody and complement factors that triggers ICD can shift the mode of macrophage activation by triggering regulated necrotic death of tumor cells. |
format | Online Article Text |
id | pubmed-8359428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83594282021-08-17 Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors Hijaze, Nizar Ledersnaider, Max Simanovich, Elina Kassem, Sameer Rahat, Michal A. J Leukoc Biol Inflammation, Extracellular Mediators, and Effector Molecules Treatment of solid tumors is often hindered by an immunosuppressive tumor microenvironment (TME) that prevents effector immune cells from eradicating tumor cells and promotes tumor progression, angiogenesis, and metastasis. Therefore, targeting components of the TME to restore the ability of immune cells to drive anti‐tumoral responses has become an important goal. One option is to induce an immunogenic cell death (ICD) of tumor cells that would trigger an adaptive anti‐tumoral immune response. Here we show that incubating mouse renal cell carcinoma (RENCA) and colon carcinoma cell lines with an anti‐extracellular matrix metalloproteinase inducer polyclonal antibody (161‐pAb) together with complement factors can induce cell death that inhibits caspase‐8 activity and enhances the phosphorylation of receptor‐interacting protein kinase 3 (RIPK3) and mixed‐lineage kinase‐like domain (MLKL). This regulated necrotic death releases high levels of dsRNA molecules to the conditioned medium (CM) relative to the necrotic death of tumor cells induced by H(2)O(2) or the apoptotic death induced by etoposide. RAW 264.7 macrophages incubated with the CM derived from these dying cells markedly enhanced the secretion of IFNβ, and enhanced their cytotoxicity. Furthermore, degradation of the dsRNA in the CM abolished the ability of RAW 264.7 macrophages to secrete IFNβ, IFNγ‐induced protein 10 (IP‐10), and TRAIL. When mice bearing RENCA tumors were immunized with the 161‐pAb, their lysates displayed elevated levels of phosphorylated RIPK3 and MLKL, as well as increased concentrations of dsRNA, IFNβ, IP‐10, and TRAIL. This shows that an antigen‐targeted therapy using an antibody and complement factors that triggers ICD can shift the mode of macrophage activation by triggering regulated necrotic death of tumor cells. John Wiley and Sons Inc. 2020-11-17 2021-08 /pmc/articles/PMC8359428/ /pubmed/33205451 http://dx.doi.org/10.1002/JLB.3A0520-333R Text en © 2020 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals LLC on behalf of Society for Leukocyte Biology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Inflammation, Extracellular Mediators, and Effector Molecules Hijaze, Nizar Ledersnaider, Max Simanovich, Elina Kassem, Sameer Rahat, Michal A. Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors |
title | Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors |
title_full | Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors |
title_fullStr | Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors |
title_full_unstemmed | Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors |
title_short | Inducing regulated necrosis and shifting macrophage polarization with anti‐EMMPRIN antibody (161‐pAb) and complement factors |
title_sort | inducing regulated necrosis and shifting macrophage polarization with anti‐emmprin antibody (161‐pab) and complement factors |
topic | Inflammation, Extracellular Mediators, and Effector Molecules |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359428/ https://www.ncbi.nlm.nih.gov/pubmed/33205451 http://dx.doi.org/10.1002/JLB.3A0520-333R |
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