دورية أكاديمية
TTK inhibitor OSU13 promotes immunotherapy responses by activating tumor STING.
| العنوان: | TTK inhibitor OSU13 promotes immunotherapy responses by activating tumor STING. |
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| المؤلفون: | Bharti V; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA., Kumar A; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA., Wang Y; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA.; Molecular Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA., Roychowdhury N; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA., de Lima Bellan D; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA., Kassaye BB; Department of Pathology., Watkins R; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA., Capece M; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA., Chung CG; Department of Pathology and Dermatology and., Hilinski G; Drug Development Institute, Comprehensive Cancer Center and The James Cancer Hospital and Solove Research Institute, Columbus, Ohio, USA., Vilgelm AE; Department of Pathology.; Pelotonia Institute for Immunooncology, and.; Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio, USA. |
| المصدر: | JCI insight [JCI Insight] 2024 Jun 20; Vol. 9 (15). Date of Electronic Publication: 2024 Jun 20. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| مواضيع طبية MeSH: | Membrane Proteins*/metabolism , Immunotherapy*/methods, Animals ; Humans ; Mice ; Cell Line, Tumor ; Female ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/drug effects ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/metabolism ; Protein Serine-Threonine Kinases/genetics ; Melanoma/drug therapy ; Melanoma/immunology ; Melanoma/pathology ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Protein-Tyrosine Kinases/metabolism ; Neoplasms/immunology ; Neoplasms/drug therapy ; Neoplasms/therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use |
| مستخلص: | TTK spindle assembly checkpoint kinase is an emerging cancer target. This preclinical study explored the antitumor mechanism of TTK inhibitor OSU13 to define a strategy for clinical development. We observed prominent antitumor activity of OSU13 in melanoma, colon and breast cancer cells, organoids derived from patients with melanoma, and mice bearing colon tumors associated with G2 cell cycle arrest, senescence, and apoptosis. OSU13-treated cells displayed DNA damage and micronuclei that triggered the cytosolic DNA-sensing cGAS/STING pathway. STING was required for the induction of several proteins involved in T cell recruitment and activity. Tumors from OSU13-treated mice showed an increased proportion of T and NK cells and evidence of PD-1/PD-L1 immune checkpoint activation. Combining a low-toxicity dose of OSU13 with anti-PD-1 checkpoint blockade resulted in prominent STING- and CD8+ T cell-dependent tumor inhibition and improved survival. These findings provide a rationale for utilizing TTK inhibitors in combination with immunotherapy in STING-proficient tumors. |
| فهرسة مساهمة: | Keywords: Cancer immunotherapy; Cell stress; Chemokines; Oncology |
| المشرفين على المادة: | 0 (Membrane Proteins) 0 (STING1 protein, human) 0 (Immune Checkpoint Inhibitors) 0 (Programmed Cell Death 1 Receptor) EC 2.7.11.1 (Protein Serine-Threonine Kinases) EC 2.7.10.1 (Protein-Tyrosine Kinases) 0 (Protein Kinase Inhibitors) |
| تواريخ الأحداث: | Date Created: 20240620 Date Completed: 20240808 Latest Revision: 20240808 |
| رمز التحديث: | 20240808 |
| DOI: | 10.1172/jci.insight.177523 |
| PMID: | 38900577 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2379-3708 |
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| DOI: | 10.1172/jci.insight.177523 |