mct-23-0039_figure_s1-s5_suppsd1-5.pptx (4.33 MB)

Figure S1-S5 from Activating an Adaptive Immune Response with a Telomerase-Mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma

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posted on 2023-06-01, 08:21 authored by Ilgen Mender, Silvia Siteni, Summer Barron, Ann Marie Flusche, Naoto Kubota, Chunhua Yu, Crystal Cornelius, Enzo Tedone, Mazvita Maziveyi, Anthony Grichuk, Niranjan Venkateswaran, Maralice Conacci-Sorrell, Yujin Hoshida, Rui Kang, Daolin Tang, Sergei Gryaznov, Jerry W. Shay

Supplementary Data

Funding

Simmons Comprehensive Cancer Center Support Grant

NIH

Cancer Prevention and Research Institute of Texas (CPRIT)

American Cancer Society (ACS)

Welch Foundation (The Welch Foundation)

NCI

National Institute of General Medical Sciences (NIGMS)

United States Department of Health and Human Services

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PB2PHD Program, UT Southwestern Medical Center Graduate School of Biomedical Sciences

History

ARTICLE ABSTRACT

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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Keywords

cancer

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CC BY

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