دورية أكاديمية
Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers.
| العنوان: | Therapeutically Active RIG-I Agonist Induces Immunogenic Tumor Cell Killing in Breast Cancers. |
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| المؤلفون: | Elion DL; Cancer Biology Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee., Jacobson ME; Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee., Hicks DJ; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Rahman B; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee., Sanchez V; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Gonzales-Ericsson PI; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee., Fedorova O; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut.; Howard Hughes Medical Institute, Chevy Chase, Maryland., Pyle AM; Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut.; Howard Hughes Medical Institute, Chevy Chase, Maryland.; Department of Chemistry, Yale University, New Haven, Connecticut., Wilson JT; Cancer Biology Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Chemical and Biomolecular Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee., Cook RS; Cancer Biology Graduate Program, Vanderbilt University School of Medicine, Nashville, Tennessee. Rebecca.cook@vanderbilt.edu.; Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.; Department of Biomedical Engineering, Vanderbilt University School of Engineering, Nashville, Tennessee. |
| المصدر: | Cancer research [Cancer Res] 2018 Nov 01; Vol. 78 (21), pp. 6183-6195. Date of Electronic Publication: 2018 Sep 17. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Baltimore, Md. : American Association for Cancer Research Original Publication: Chicago [etc.] |
| مواضيع طبية MeSH: | Gene Expression Regulation, Neoplastic*, Breast Neoplasms/*immunology , Breast Neoplasms/*therapy , DEAD Box Protein 58/*metabolism, Animals ; Apoptosis ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cytokines/metabolism ; Female ; Gene Expression Profiling ; Humans ; Immunity, Innate ; Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/metabolism ; MCF-7 Cells ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nanoparticles/chemistry ; Neoplasm Metastasis ; Neoplasms/metabolism ; Pyroptosis ; Receptors, Immunologic ; Signal Transduction ; Tumor Microenvironment |
| مستخلص: | Cancer immunotherapies that remove checkpoint restraints on adaptive immunity are gaining clinical momentum but have not achieved widespread success in breast cancers, a tumor type considered poorly immunogenic and which harbors a decreased presence of tumor-infiltrating lymphocytes. Approaches that activate innate immunity in breast cancer cells and the tumor microenvironment are of increasing interest, based on their ability to induce immunogenic tumor cell death, type I IFNs, and lymphocyte-recruiting chemokines. In agreement with reports in other cancers, we observe loss, downregulation, or mutation of the innate viral nucleotide sensor retinoic acid-inducible gene I (RIG-I/ DDX58 ) in only 1% of clinical breast cancers, suggesting potentially widespread applicability for therapeutic RIG-I agonists that activate innate immunity. This was tested using an engineered RIG-I agonist in a breast cancer cell panel representing each of three major clinical breast cancer subtypes. Treatment with RIG-I agonist resulted in upregulation and mitochondrial localization of RIG-I and activation of proinflammatory transcription factors STAT1 and NF-κB. RIG-I agonist triggered the extrinsic apoptosis pathway and pyroptosis, a highly immunogenic form of cell death in breast cancer cells. RIG-I agonist also induced expression of lymphocyte-recruiting chemokines and type I IFN, confirming that cell death and cytokine modulation occur in a tumor cell-intrinsic manner. Importantly, RIG-I activation in breast tumors increased tumor lymphocytes and decreased tumor growth and metastasis. Overall, these findings demonstrate successful therapeutic delivery of a synthetic RIG-I agonist to induce tumor cell killing and to modulate the tumor microenvironment in vivo Significance: These findings describe the first in vivo delivery of RIG-I mimetics to tumors, demonstrating a potent immunogenic and therapeutic effect in the context of otherwise poorly immunogenic breast cancers. Cancer Res; 78(21); 6183-95. ©2018 AACR . (©2018 American Association for Cancer Research.) |
| المشرفين على المادة: | 0 (Cytokines) 0 (Receptors, Immunologic) EC 3.6.1.- (RIGI protein, human) EC 3.6.4.13 (DEAD Box Protein 58) |
| تواريخ الأحداث: | Date Created: 20180919 Date Completed: 20191007 Latest Revision: 20231213 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1158/0008-5472.CAN-18-0730 |
| PMID: | 30224377 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-7445 |
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| DOI: | 10.1158/0008-5472.CAN-18-0730 |