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TREX1 Inactivation Unleashes Cancer Cell STING-Interferon Signaling and Promotes Antitumor Immunity.
Tani, Tetsuo; Mathsyaraja, Haritha; Campisi, Marco; Li, Ze-Hua; Haratani, Koji; Fahey, Caroline G; Ota, Keiichi; Mahadevan, Navin R; Shi, Yingxiao; Saito, Shin; Mizuno, Kei; Thai, Tran C; Sasaki, Nobunari; Homme, Mizuki; Yusuf, Choudhury Fabliha B; Kashishian, Adam; Panchal, Jipsa; Wang, Min; Wolf, Benjamin J; Barbie, Thanh U; Paweletz, Cloud P; Gokhale, Prafulla C; Liu, David; Uppaluri, Ravindra; Kitajima, Shunsuke; Cain, Jennifer; Barbie, David A.
Afiliação
  • Tani T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Mathsyaraja H; Gilead Sciences, Foster City, California.
  • Campisi M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Li ZH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Haratani K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Fahey CG; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Ota K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Mahadevan NR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Shi Y; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
  • Saito S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Mizuno K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Thai TC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Sasaki N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Homme M; Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Yusuf CFB; Department of Cell Biology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
  • Kashishian A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Panchal J; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Wang M; Gilead Sciences, Foster City, California.
  • Wolf BJ; Gilead Sciences, Foster City, California.
  • Barbie TU; Gilead Sciences, Foster City, California.
  • Paweletz CP; Gilead Sciences, Foster City, California.
  • Gokhale PC; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Liu D; Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • Uppaluri R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Kitajima S; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Cain J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Barbie DA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Discov ; 14(5): 752-765, 2024 May 01.
Article em En | MEDLINE | ID: mdl-38227896
ABSTRACT
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.

SIGNIFICANCE:

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. This article is featured in Selected Articles from This Issue, p. 695.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Transdução de Sinais / Exodesoxirribonucleases / Proteínas de Membrana Limite: Animals / Humans Idioma: En Revista: Cancer Discov Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfoproteínas / Transdução de Sinais / Exodesoxirribonucleases / Proteínas de Membrana Limite: Animals / Humans Idioma: En Revista: Cancer Discov Ano de publicação: 2024 Tipo de documento: Article