Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy
Background High-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical...
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BMJ Publishing Group
2021-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/3/e001966.full |
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| author | Coraline Radermecker Pascale Hubert Patrick Roncarati Stephanie Demoulin Charlotte Pilard Marie Ancion Celia Reynders Thomas Lerho Diane Bruyere Alizee Lebeau Margot Meunier Marie-Julie Nokin Elodie Hendrick Olivier Peulen Philippe Delvenne Michael Herfs |
| author_facet | Coraline Radermecker Pascale Hubert Patrick Roncarati Stephanie Demoulin Charlotte Pilard Marie Ancion Celia Reynders Thomas Lerho Diane Bruyere Alizee Lebeau Margot Meunier Marie-Julie Nokin Elodie Hendrick Olivier Peulen Philippe Delvenne Michael Herfs |
| author_sort | Coraline Radermecker |
| collection | DOAJ |
| description | Background High-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.Methods HMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined.Results Associated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45+) immune cells, drastic reductions of monocytic/granulocytic myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes, a higher M1/M2 ratio of macrophages as well as an increased activation of both DC and pDC were continually observed following HMGB1 inhibition. Moreover, blocking HMGB1 improved the efficacy of anti-PD-1 cancer monoimmunotherapy. We also reported that a significant fraction of HMGB1 encountered within cancer microenvironment (interstitial fluids) is oxidized and, in opposite to its reduced isoform, oxidized HMGB1 acts as a tolerogenic signal in a receptor for advanced glycation endproducts-dependent manner.Conclusion Collectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response. |
| format | Article |
| id | doaj-art-5abeedf920fe45b2a2fd8b6a724064eb |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-5abeedf920fe45b2a2fd8b6a724064eb2025-02-02T23:35:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-03-019310.1136/jitc-2020-001966Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapyCoraline Radermecker0Pascale Hubert1Patrick Roncarati2Stephanie Demoulin3Charlotte Pilard4Marie Ancion5Celia Reynders6Thomas Lerho7Diane Bruyere8Alizee Lebeau9Margot Meunier10Marie-Julie Nokin11Elodie Hendrick12Olivier Peulen13Philippe Delvenne14Michael Herfs153 Faculty of Veterinary Medicine, University of Liège, Liège, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Immunophysiology, GIGA-I3, University of Liege, Liege, BelgiumMetastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumMetastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumLaboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, BelgiumBackground High-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.Methods HMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined.Results Associated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45+) immune cells, drastic reductions of monocytic/granulocytic myeloid-derived suppressor cells (MDSC) and regulatory T lymphocytes, a higher M1/M2 ratio of macrophages as well as an increased activation of both DC and pDC were continually observed following HMGB1 inhibition. Moreover, blocking HMGB1 improved the efficacy of anti-PD-1 cancer monoimmunotherapy. We also reported that a significant fraction of HMGB1 encountered within cancer microenvironment (interstitial fluids) is oxidized and, in opposite to its reduced isoform, oxidized HMGB1 acts as a tolerogenic signal in a receptor for advanced glycation endproducts-dependent manner.Conclusion Collectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response.https://jitc.bmj.com/content/9/3/e001966.full |
| spellingShingle | Coraline Radermecker Pascale Hubert Patrick Roncarati Stephanie Demoulin Charlotte Pilard Marie Ancion Celia Reynders Thomas Lerho Diane Bruyere Alizee Lebeau Margot Meunier Marie-Julie Nokin Elodie Hendrick Olivier Peulen Philippe Delvenne Michael Herfs Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy Journal for ImmunoTherapy of Cancer |
| title | Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy |
| title_full | Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy |
| title_fullStr | Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy |
| title_full_unstemmed | Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy |
| title_short | Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy |
| title_sort | extracellular hmgb1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor based immunotherapy |
| url | https://jitc.bmj.com/content/9/3/e001966.full |
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