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Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity.

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.

SUBMITTER: Mender I

PROVIDER: S-EPMC7494563 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity.

Mender Ilgen I Zhang Anli A Ren Zhenhua Z Han Chuanhui C Deng Yafang Y Siteni Silvia S Li Huiyu H Zhu Jiankun J Vemula Aishwarya A Shay Jerry W JW Fu Yang-Xin YX

Cancer cell 20200702 3

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 ...[more]

PMID: 32619407

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