RETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer

被引:0
|
作者
Jeffrey Patterson-Fortin
Heta Jadhav
Constantia Pantelidou
Tin Phan
Carter Grochala
Anita K. Mehta
Jennifer L. Guerriero
Gerburg M. Wulf
Brian M. Wolpin
Ben Z. Stanger
Andrew J. Aguirre
James M. Cleary
Alan D. D’Andrea
Geoffrey I. Shapiro
机构
[1] Dana-Farber Cancer Institute,Department of Medical Oncology
[2] Brigham and Women’s Hospital and Harvard Medical School,Department of Medicine
[3] Dana-Farber Cancer Institute and Harvard Medical School,Department of Radiation Oncology
[4] Brigham and Women’s Hospital,Department of Surgical Oncology and Harvard Medical School
[5] Beth Israel Deaconess Medical Center and Harvard Medical School,Department of Medicine, Division of Hematology
[6] Dana-Farber Cancer Institute,Oncology
[7] University of Pennsylvania Perelman School of Medicine,Hale Family Center for Pancreatic Cancer Research
[8] Dana-Farber Cancer Institute,Department of Medicine, Division of Gastroenterology, Abramson Family Cancer Research Institute
[9] Bayer Pharmaceuticals,Center for DNA Damage and Repair
[10] Arpeggio,undefined
[11] Sanofi,undefined
来源
Nature Communications | / 14卷
关键词
D O I
暂无
中图分类号
学科分类号
摘要
Recently developed inhibitors of polymerase theta (POLθ) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POLθ inhibition in immunocompetent models of BRCA1-deficient triple-negative breast cancer (TNBC) or BRCA2-deficient pancreatic ductal adenocarcinoma (PDAC). We demonstrate that genetic POLQ depletion or pharmacological POLθ inhibition induces both innate and adaptive immune responses in these models. POLθ inhibition resulted in increased micronuclei, cGAS/STING pathway activation, type I interferon gene expression, CD8+ T cell infiltration and activation, local paracrine activation of dendritic cells and upregulation of PD-L1 expression. Depletion of CD8+ T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.
引用
收藏
相关论文
共 24 条
  • [1] RETRACTED: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer (Retracted Article)
    Patterson-Fortin, Jeffrey
    Jadhav, Heta
    Pantelidou, Constantia
    Phan, Tin
    Grochala, Carter
    Mehta, Anita K.
    Guerriero, Jennifer L.
    Wulf, Gerburg M.
    Wolpin, Brian M.
    Stanger, Ben Z.
    Aguirre, Andrew J.
    Cleary, James M.
    D'Andrea, Alan D.
    Shapiro, Geoffrey I.
    NATURE COMMUNICATIONS, 2023, 14 (01)
  • [2] Retraction Note: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer
    Jeffrey Patterson-Fortin
    Heta Jadhav
    Constantia Pantelidou
    Tin Phan
    Carter Grochala
    Anita K. Mehta
    Jennifer L. Guerriero
    Gerburg M. Wulf
    Brian M. Wolpin
    Ben Z. Stanger
    Andrew J. Aguirre
    James M. Cleary
    Alan D. D’Andrea
    Geoffrey I. Shapiro
    Nature Communications, 14
  • [3] Polymerase theta inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in BRCA-deficient cancers
    Patterson-Fortin, Jeffrey
    Jadhav, Heta
    Pantelidou, Constantia
    Phan, Tin
    Grochala, Carter
    Mehta, Anita K.
    Guerriero, Jennifer L.
    Wulf, Gerburg M.
    Wolpin, Brian M.
    Stanger, Ben Z.
    Aguirre, Andrew J.
    Cleary, James M.
    D'Andrea, Alan D.
    Shapiro, Geoffrey I.
    CANCER RESEARCH, 2023, 83 (07)
  • [4] RETRACTION: Polymerase. inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer (Retraction of Vol 14, art no 1390, 2023)
    Patterson-Fortin, Jeffrey
    Jadhav, Heta
    Pantelidou, Constantia
    Tin Phan
    Grochala, Carter
    Mehta, Anita K.
    Guerriero, Jennifer L.
    Wulf, Gerburg M.
    Wolpin, Brian M.
    Stanger, Ben Z.
    Aguirre, Andrew J.
    Cleary, James M.
    D'Andrea, Alan D.
    Shapiro, Geoffrey I.
    NATURE COMMUNICATIONS, 2023, 14 (01)
  • [5] Polymerase theta inhibition activates the cGAS-STING signaling pathway and elicits an immune response in homologous recombination-deficient pancreatic adenocarcinoma.
    Oh, Grace
    Wang, Annie
    Wang, Lidong
    Li, Jiufeng
    Werba, Gregor
    Weissinger, Daniel
    Zhao, Ende
    Dhara, Surajit
    Hernandez, Rosmel
    Ackermann, Amanda
    Kalfakakou, Despoina
    Kawaler, Emily A.
    Golan, Talia
    Welling, Theodore H.
    Sfeir, Agnel
    Simeone, Diane M.
    CANCER RESEARCH, 2022, 82 (22) : 102 - 102
  • [6] Nanomotors activating both cGAS-STING pathway and immune checkpoint blockade for tumor therapy and bioimaging
    Jing, Dan
    Zhang, Ji
    Li, Ziyi
    Yan, Wennan
    Guo, Yingshu
    TALANTA, 2025, 284
  • [7] A metal-organic nanoframework for efficient colorectal cancer immunotherapy by the cGAS-STING pathway activation and immune checkpoint blockade
    Zhang, Xiaodian
    Tian, Hailong
    Chen, Yang
    Liang, Baichuan
    Nice, Edouard C.
    Huang, Canhua
    Xie, Na
    Zheng, Shaojiang
    JOURNAL OF NANOBIOTECHNOLOGY, 2024, 22 (01)
  • [8] Precisely Activating cGAS-STING Pathway with a Novel Peptide-Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy
    Xing, Yumeng
    Peng, Ao
    Yang, Jianhui
    Cheng, Zhifei
    Yue, Yi
    Liu, Feilong
    Li, Fenghe
    Liu, Yang
    Liu, Qi
    ADVANCED SCIENCE, 2024, 11 (15)
  • [9] Phase I study combining PARP-inhibition with immune checkpoint blockade in women with BRCA-deficient recurrent ovarian cancer
    Adams, S. F.
    Rixe, O.
    McCance, D.
    Lee, J. H.
    Eberhardt, S.
    Westgate, S.
    Rutledge, T.
    Muller, C.
    GYNECOLOGIC ONCOLOGY, 2017, 145 : 99 - 100
  • [10] The PARP inhibitor rucaparib activates the STING pathway and enhances antitumor responses of immune checkpoint inhibitors in BRCA deficient syngeneic models
    Minh Nguyen
    Robillard, Liliane
    Lin, Kevin K.
    Harding, Thomas C.
    Simmons, Andrew D.
    CANCER RESEARCH, 2018, 78 (13)