Cancer Cell
Volume 38, Issue 3, 14 September 2020, Pages 400-411.e6
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Article
Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity

https://doi.org/10.1016/j.ccell.2020.05.020Get rights and content
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Highlights

  • 6-thio-dG induces telomere-associated DNA damage in telomerase-positive tumor cells

  • 6-thio-dG reduces tumor burden in T cell-dependent manner in syngeneic tumor models

  • Host STING signaling is required for 6-thio-dG-mediated anti-tumor effects

  • 6-thio-dG overcomes PD-L1 blockade resistance in advanced tumors

Summary

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

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

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These authors contributed equally

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