دورية أكاديمية
أعرض في EDS

Targeting TBK1 to overcome resistance to cancer immunotherapy.

التفاصيل البيبلوغرافية
العنوان: Targeting TBK1 to overcome resistance to cancer immunotherapy.
المؤلفون: Sun Y; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Revach OY; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Anderson S; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kessler EA; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Wolfe CH; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jenney A; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA., Mills CE; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA., Robitschek EJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Davis TGR; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kim S; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Fu A; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Ma X; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Gwee J; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Tiwari P; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Du PP; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Sindurakar P; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Tian J; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Mehta A; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Schneider AM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Yizhak K; Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Institute of Technology, Technion, Haifa, Israel., Sade-Feldman M; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., LaSalle T; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Sharova T; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Xie H; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Liu S; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA., Michaud WA; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Saad-Beretta R; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Yates KB; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Iracheta-Vellve A; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Spetz JKE; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.; John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA., Qin X; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.; John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA., Sarosiek KA; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.; John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA., Zhang G; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.; Preston Robert Tisch Brain Tumor Center, Department of Pathology, Duke University School of Medicine, Durham, NC, USA., Kim JW; Moores Cancer Center, UC San Diego, La Jolla, CA, USA.; Center for Novel Therapeutics, UC San Diego, La Jolla, CA, USA.; Department of Medicine, UC San Diego, La Jolla, CA, USA., Su MY; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Cicerchia AM; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Rasmussen MQ; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Klempner SJ; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Juric D; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Pai SI; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.; Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA., Miller DM; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Giobbie-Hurder A; Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA., Chen JH; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA., Pelka K; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Frederick DT; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Stinson S; Gilead Sciences, Foster City, CA, USA., Ivanova E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA., Aref AR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.; Xsphera Biosciences, Boston, MA, USA., Paweletz CP; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA., Barbie DA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA., Sen DR; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Fisher DE; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Corcoran RB; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Hacohen N; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Sorger PK; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA., Flaherty KT; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Boland GM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA., Manguso RT; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jenkins RW; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. rjenkins@mgh.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. rjenkins@mgh.harvard.edu.; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA. rjenkins@mgh.harvard.edu.
المصدر: Nature [Nature] 2023 Mar; Vol. 615 (7950), pp. 158-167. Date of Electronic Publication: 2023 Jan 12.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
أسماء مطبوعة: Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
مواضيع طبية MeSH: Immune Evasion*/genetics , Immune Evasion*/immunology , Immunotherapy*/methods , Protein Serine-Threonine Kinases*/antagonists & inhibitors , Protein Serine-Threonine Kinases*/genetics , Drug Resistance, Neoplasm*, Humans ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Organoids ; Tumor Necrosis Factors/immunology ; Interferon-gamma/immunology ; Spheroids, Cellular ; Caspases ; Janus Kinases ; STAT Transcription Factors
مستخلص: Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking 1,2 . Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1) 3 as a candidate immune-evasion gene in a pooled genetic screen 4 . Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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معلومات مُعتمدة: R01 AR072304 United States AR NIAMS NIH HHS; R01 DK125263 United States DK NIDDK NIH HHS; P01 CA163222 United States CA NCI NIH HHS; T32 GM007753 United States GM NIGMS NIH HHS; P01 CA240239 United States CA NCI NIH HHS; R37 CA248565 United States CA NCI NIH HHS; T32 CA207021 United States CA NCI NIH HHS; K99 CA259511 United States CA NCI NIH HHS; K08 CA226391 United States CA NCI NIH HHS; R01 CA222871 United States CA NCI NIH HHS; R01 AR043369 United States AR NIAMS NIH HHS
المشرفين على المادة: 0 (Programmed Cell Death 1 Receptor)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (TBK1 protein, human)
0 (PDCD1 protein, human)
0 (Tumor Necrosis Factors)
82115-62-6 (Interferon-gamma)
EC 3.4.22.- (Caspases)
EC 2.7.10.2 (Janus Kinases)
0 (STAT Transcription Factors)
تواريخ الأحداث: Date Created: 20230112 Date Completed: 20230316 Latest Revision: 20240607
رمز التحديث: 20240607
مُعرف محوري في PubMed: PMC10171827
DOI: 10.1038/s41586-023-05704-6
PMID: 36634707
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4687
DOI:10.1038/s41586-023-05704-6