دورية أكاديمية
أعرض في EDS

Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway.

التفاصيل البيبلوغرافية
العنوان: Cytosolic DNA accumulation promotes breast cancer immunogenicity via a STING-independent pathway.
المؤلفون: Zhang J; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA zhangjing@him.cas.cn sylin@mdanderson.org., Dai H; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Huo L; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Burks JK; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., McGrail DJ; Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, Texas, USA.; Lerner Research Institute, Cleveland Clinic, Cleveland, Texas, USA., Lin SY; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA zhangjing@him.cas.cn sylin@mdanderson.org.
المصدر: Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Oct; Vol. 11 (10).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
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: Triple Negative Breast Neoplasms*/drug therapy , Triple Negative Breast Neoplasms*/genetics, Animals ; Humans ; Mice ; DNA ; Immunity, Innate ; Lymphocytes, Tumor-Infiltrating
مستخلص: Background: Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed.
Methods: Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting tumor immunogenicity and antitumor immune response was evaluated using murine breast cancer models.
Results: We found the tumorous cytosolic ssDNA is associated with tumor-infiltrating lymphocyte in patients with triple negative breast cancer. TREX1 deficiency triggered a STING-independent innate immune response via DDX3X. Cytosolic ssDNA accumulation in tumors due to TREX1 deletion is sufficient to drastically improve the efficacy of ICB. We further identified a cytosolic ssDNA inducer CEP-701, which sensitized breast tumors to ICB without the toxicities associated with inhibiting DNA damage response.
Conclusions: This work demonstrated that cytosolic ssDNA accumulation promotes breast cancer immunogenicity and may be a novel therapeutic strategy to improve the efficacy of ICB with minimal toxicities.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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معلومات مُعتمدة: R00 CA240689 United States CA NCI NIH HHS; R01 CA247862 United States CA NCI NIH HHS; R50 CA243707 United States CA NCI NIH HHS
فهرسة مساهمة: Keywords: breast neoplasms; immunotherapy
المشرفين على المادة: 9007-49-2 (DNA)
0 (STING1 protein, human)
0 (Sting1 protein, mouse)
تواريخ الأحداث: Date Created: 20231031 Date Completed: 20231103 Latest Revision: 20240702
رمز التحديث: 20240702
مُعرف محوري في PubMed: PMC10619126
DOI: 10.1136/jitc-2023-007560
PMID: 37907220
قاعدة البيانات: MEDLINE
الوصف
تدمد:2051-1426
DOI:10.1136/jitc-2023-007560