Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity

Cancer Cell. 2020 Sep 14;38(3):400-411.e6. doi: 10.1016/j.ccell.2020.05.020. Epub 2020 Jul 2.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity / drug effects
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Deoxyguanosine / analogs & derivatives*
  • Deoxyguanosine / pharmacology
  • Deoxyguanosine / therapeutic use
  • HCT116 Cells
  • Humans
  • Immunity, Innate / drug effects
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Telomerase / antagonists & inhibitors*
  • Telomerase / metabolism
  • Telomere / enzymology
  • Telomere / genetics*
  • Thionucleosides / pharmacology*
  • Thionucleosides / therapeutic use
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Tumor Burden / immunology

Substances

  • Membrane Proteins
  • STING1 protein, human
  • Thionucleosides
  • alpha-2'-deoxythioguanosine
  • Telomerase
  • Deoxyguanosine