Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity

Ilgen Mender, Anli Zhang, Zhenhua Ren, Chuanhui Han, Yafang Deng, Silvia Siteni, Huiyu Li, Jiankun Zhu, Aishwarya Vemula, Jerry W. Shay, Yang Xin Fu

Research output: Contribution to journalArticle

Abstract

Telomerase is an attractive target for anti-tumor therapy as it is almost universally expressed in cancer cells. Here, we show that treatment with a telomere-targeting drug, 6-thio-2′-deoxyguanosine (6-thio-dG), leads to tumor regression through innate and adaptive immune-dependent responses in syngeneic and humanized mouse models of telomerase-expressing cancers. 6-thio-dG treatment causes telomere-associated DNA damages that are sensed by dendritic cells (DCs) and activates the host cytosolic DNA sensing STING/interferon I pathway, resulting in enhanced cross-priming capacity of DCs and tumor-specific CD8+ T cell activation. Moreover, 6-thio-dG overcomes resistance to checkpoint blockade in advanced cancer models. Our results unveil how telomere stress increases innate sensing and adaptive anti-tumor immunity and provide strong rationales for combining telomere-targeting therapy with immunotherapy.

Original languageEnglish (US)
Pages (from-to)400-411.e6
JournalCancer Cell
Volume38
Issue number3
DOIs
StatePublished - Sep 14 2020

Keywords

  • 6-thio-dG
  • DNA damage
  • PD-1/PD-L1
  • STING
  • anti-tumor immunity
  • checkpoint blockade
  • immunotherapy
  • innate sensing
  • telomerase
  • telomere-targeting therapy

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Mender, I., Zhang, A., Ren, Z., Han, C., Deng, Y., Siteni, S., Li, H., Zhu, J., Vemula, A., Shay, J. W., & Fu, Y. X. (2020). Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity. Cancer Cell, 38(3), 400-411.e6. https://doi.org/10.1016/j.ccell.2020.05.020