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أعرض في EDS

Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy.

التفاصيل البيبلوغرافية
العنوان: Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy.
المؤلفون: Hubert P; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Roncarati P; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Demoulin S; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Pilard C; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Ancion M; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Reynders C; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Lerho T; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Bruyere D; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Lebeau A; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Radermecker C; Laboratory of Immunophysiology, GIGA-I3, University of Liege, Liege, Belgium.; Faculty of Veterinary Medicine, University of Liege, Liege, Belgium., Meunier M; Laboratory of Immunophysiology, GIGA-I3, University of Liege, Liege, Belgium.; Faculty of Veterinary Medicine, University of Liege, Liege, Belgium., Nokin MJ; Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium., Hendrick E; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium., Peulen O; Metastasis Research Laboratory, GIGA-Cancer, University of Liege, Liege, Belgium., Delvenne P; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium.; Department of Pathology, University Hospital Center of Liege, Liege, Belgium., Herfs M; Laboratory of Experimental Pathology, GIGA-Cancer, University of Liege, Liege, Belgium M.Herfs@uliege.be.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2021 Mar; Vol. 9 (3).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: BMJ Publishing Group Ltd Country of Publication: England NLM ID: 101620585 Publication Model: Print Cited Medium: Internet ISSN: 2051-1426 (Electronic) Linking ISSN: 20511426 NLM ISO Abbreviation: J Immunother Cancer Subsets: MEDLINE
أسماء مطبوعة: Publication: 2020- : London, United Kingdom : BMJ Publishing Group Ltd.
Original Publication: London : BioMed Central, 2013-
مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*pharmacology , Breast Neoplasms/*drug therapy , Carcinoma, Non-Small-Cell Lung/*drug therapy , Glycyrrhizic Acid/*pharmacology , HMGB1 Protein/*antagonists & inhibitors , Immune Checkpoint Inhibitors/*pharmacology , Lung Neoplasms/*drug therapy , Peptide Fragments/*pharmacology , S100 Proteins/*pharmacology , Tumor Microenvironment/*immunology , Uterine Cervical Neoplasms/*drug therapy, Adaptive Immunity/drug effects ; Animals ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Carcinoma, Non-Small-Cell Lung/immunology ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Line, Tumor ; Female ; HMGB1 Protein/metabolism ; Humans ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; RAW 264.7 Cells ; Signal Transduction ; Tumor Burden/drug effects ; Uterine Cervical Neoplasms/immunology ; Uterine Cervical Neoplasms/metabolism ; Uterine Cervical Neoplasms/pathology
مستخلص: 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.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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فهرسة مساهمة: Keywords: breast neoplasms; translational medical research; tumor microenvironment
المشرفين على المادة: 0 (HMGB1 Protein)
0 (HMGB1 protein, human)
0 (HMGB1 protein, mouse)
0 (Immune Checkpoint Inhibitors)
0 (Peptide Fragments)
0 (S100 Proteins)
0 (glutamyl-leucyl-lysyl-valyl-leucyl-methionyl-glutamyl-lysyl-glutamyl-leucine)
6FO62043WK (Glycyrrhizic Acid)
تواريخ الأحداث: Date Created: 20210313 Date Completed: 20211217 Latest Revision: 20211217
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7959241
DOI: 10.1136/jitc-2020-001966
PMID: 33712445
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2020-001966