Activating an Adaptive Immune Response with a Telomerase-mediated Telomere Targeting Therapeutic in Hepatocellular Carcinoma.

A select group of hepatocellular carcinomas (HCC) patients benefit from surgical, radiological, and systemic therapies that include a combination of anti-angiogenic and immune-checkpoint inhibitors. However, since 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 anti-tumor immunity in HCC. Importantly, the extracellular HMGB1 (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.