<i>TREX1</i> Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity

DOI PDF PDF PDF 参考文献32件
  • Tetsuo Tani
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Haritha Mathsyaraja
    2Gilead Sciences, Foster City, California.
  • Marco Campisi
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Ze-Hua Li
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Koji Haratani
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Caroline G. Fahey
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Keiichi Ota
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Navin R. Mahadevan
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Yingxiao Shi
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Shin Saito
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Kei Mizuno
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Tran C. Thai
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Nobunari Sasaki
    4Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Mizuki Homme
    4Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Choudhury Fabliha B. Yusuf
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Adam Kashishian
    2Gilead Sciences, Foster City, California.
  • Jipsa Panchal
    2Gilead Sciences, Foster City, California.
  • Min Wang
    2Gilead Sciences, Foster City, California.
  • Benjamin J. Wolf
    2Gilead Sciences, Foster City, California.
  • Thanh U. Barbie
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Cloud P. Paweletz
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Prafulla C. Gokhale
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • David Liu
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Ravindra Uppaluri
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Shunsuke Kitajima
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Jennifer Cain
    2Gilead Sciences, Foster City, California.
  • David A. Barbie
    1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

説明

<jats:title>Abstract</jats:title> <jats:sec> <jats:title/> <jats:p>A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING–IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell–derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING–IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>STING–IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell–mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance.</jats:p> <jats:p>This article is featured in Selected Articles from This Issue, p. 695</jats:p> </jats:sec>

収録刊行物

  • Cancer Discovery

    Cancer Discovery 14 (5), 752-765, 2024-01-10

    American Association for Cancer Research (AACR)

参考文献 (32)*注記

もっと見る

関連プロジェクト

もっと見る

問題の指摘

ページトップへ