Telomere Stress Potentiates STING-Dependent Anti-tumor Immunity
Menée à l'aide de modèles murins de tumeurs surexprimant la télomérase, cette étude met en évidence un mécanisme par lequel la 6-thio-2′-désoxyguanosine, un médicament ciblant les télomères, favorise l'immunité antitumorale dépendante de la voie de signalisation de la protéine STING
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.
Cancer Cell 2020