TY - JOUR
T1 - Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma
AU - Mender, Ilgen
AU - Siteni, Silvia
AU - Barron, Summer
AU - Flusche, Ann Marie
AU - Kubota, Naoto
AU - Yu, Chunhua
AU - Cornelius, Crystal
AU - Tedone, Enzo
AU - Maziveyi, Mazvita
AU - Grichuk, Anthony
AU - Venkateswaran, Niranjan
AU - Conacci-Sorrell, Maralice
AU - Hoshida, Yujin
AU - Kang, Rui
AU - Tang, Daolin
AU - Gryaznov, Sergei
AU - Shay, Jerry W.
N1 - Publisher Copyright:
©2023 The Authors; Published by the American Association for Cancer Research.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5'-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.
AB - A select group of patients with hepatocellular carcinomas (HCC) benefit from surgical, radiologic, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, because HCC is generally asymptomatic in its early stages, this not only leads to late diagnosis, but also to therapy resistance. The nucleoside analogue 6-thio-dG (THIO) is a first-in-class telomerase-mediated telomere-targeting anticancer agent. In telomerase expressing cancer cells, THIO is converted into the corresponding 5'-triphosphate, which is efficiently incorporated into telomeres by telomerase, activating telomere damage responses and apoptotic pathways. Here, we show how THIO is effective in controlling tumor growth and, when combined with immune checkpoint inhibitors, is even more effective in a T-cell-dependent manner. We also show telomere stress induced by THIO increases both innate sensing and adaptive antitumor immunity in HCC. Importantly, the extracellular high-mobility group box 1 protein acts as a prototypical endogenous DAMP (Damage Associated Molecular Pattern) in eliciting adaptive immunity by THIO. These results provide a strong rationale for combining telomere-targeted therapy with immunotherapy.
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U2 - 10.1158/1535-7163.MCT-23-0039
DO - 10.1158/1535-7163.MCT-23-0039
M3 - Article
C2 - 37070671
AN - SCOPUS:85160965000
SN - 1535-7163
VL - 22
SP - 737
EP - 750
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 6
ER -