@article{a301279743c247ae81ea33ff5622e546,
title = "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.",
keywords = "6-thio-dG, DNA damage, PD-1/PD-L1, STING, anti-tumor immunity, checkpoint blockade, immunotherapy, innate sensing, telomerase, telomere-targeting therapy",
author = "Ilgen Mender and Anli Zhang and Zhenhua Ren and Chuanhui Han and Yafang Deng and Silvia Siteni and Huiyu Li and Jiankun Zhu and Aishwarya Vemula and Shay, {Jerry W.} and Fu, {Yang Xin}",
note = "Funding Information: This work was in part supported by Texas CPRIT , United States ( RR150072 and RP180725 ) to Y.-X.F. and NCI SPORE , United States ( P50CA70907 ), NIH , United States ( C06 RR30414 ), Harold Simmons National Cancer Institute Designated Comprehensive Cancer Center Support Grant ( CA142543 ), United States to J.W.S. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. J.W.S. holds the distinguished Southland Financial Corporation Distinguished Chair in Geriatrics Research. We acknowledge Jaewon Min and Peter Ly for technical help and the Cancer Biology Training Grant, NCI, United States, T32CA124334 (to I.M.), Cancer Intervention and Prevention Discovery Training Program Fellowship, United States, RP160157 (to I.M. and S.S.). We also thank Zhida Liu, Longchao Liu, Xuezhi Cao, Changzheng Lu, and Jian Qiao for providing experiment materials and helpful discussions. Funding Information: This work was in part supported by Texas CPRIT, United States (RR150072 and RP180725) to Y.-X.F. and NCI SPORE, United States (P50CA70907), NIH, United States (C06 RR30414), Harold Simmons National Cancer Institute Designated Comprehensive Cancer Center Support Grant (CA142543), United States to J.W.S. Y.-X.F. holds the Mary Nell and Ralph B. Rogers Professorship in Immunology. J.W.S. holds the distinguished Southland Financial Corporation Distinguished Chair in Geriatrics Research. We acknowledge Jaewon Min and Peter Ly for technical help and the Cancer Biology Training Grant, NCI, United States, T32CA124334 (to I.M.), Cancer Intervention and Prevention Discovery Training Program Fellowship, United States, RP160157 (to I.M. and S.S.). We also thank Zhida Liu, Longchao Liu, Xuezhi Cao, Changzheng Lu, and Jian Qiao for providing experiment materials and helpful discussions. Conceptualization, A.Z. J.W.S. and Y.-X.F.; Methodology, A.Z. I.M. Z.R. and C.H.; Investigation, A.Z. I.M. Z.R. Y.D. S.S. H.L. and A.V.; Writing – Original Draft, A.Z. I.M. and Z.R.; Writing – Review & Editing, J.W.S. and Y.-X.F.; Funding Acquisition, J.W.S. and Y.-X.F.; Resources, C.H. and J.Z.; Supervision, A.Z. J.W.S. and Y.-X.F. J.W.S. is a founding scientist of Maia Biotechnology who is progressing 6-thio-dG into clinical development. In addition, J.W.S. A.Z. I.M. and Y.-X.F. are named co-inventors on pending patents related to this work. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = sep,
day = "14",
doi = "10.1016/j.ccell.2020.05.020",
language = "English (US)",
volume = "38",
pages = "400--411.e6",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}