Abstract 4143: Enhancing adaptive immune responses with telomerase-mediated telomere targeting therapeutics in hepatocellular carcinoma

Abstract

Abstract Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and is the third leading cause of cancer-related deaths. In recent years, immune checkpoint inhibitors (ICIs) have improved treatment of solid tumors including HCC. However, due to low response rates with current standard of care immunotherapy and angiogenic inhibitors, there is an urgent need to develop new therapeutic strategies to improve the efficacy of immunotherapy against HCC. Our lab has shown that 6-thio-2’ deoxyguanosine (6-thio-dG), a telomerase-mediated telomere targeting agent, is incorporated into newly synthesized telomeres by telomerase and causes rapid telomere uncapping, thereby inducing telomere-associated DNA damage in cancer cells. These damaged DNA fragments can then lead to enhanced adaptive immune responses. In this study, we evaluated the therapeutic effects of 6-thio-dG in vitro and in vivo together with ICIs in liver tumors to determine whether combining immunotherapy with a telomere-targeting agent could serve as an effective strategy for HCC. To explore whether 6-thio-dG is effective in killing liver cancer cells, we ran cell viability and telomere dysfunction induced foci (TIF) assays to assess DNA damage on telomeres in vitro and compared tumor volumes of mice following 6-thio-dG monotherapy, immunotherapy, and sequential treatment of 6-thio-dG and immunotherapy in syngeneic mouse models. We observed that 6-thio-dG reduced cell viability and induced telomere dysfunction in a panel of human and mouse liver cancer cells. In addition, 6-thio-dG enhanced the therapeutic effect of immunotherapies in liver syngeneic mouse models. Overall, our findings show that the telomere-targeting anticancer agent 6-thio-dG inhibits HCC as a single monotherapy and/or sequential therapy together with immunotherapies. These results provide an experimental rationale for a potentially new immunochemotherapy strategy based on the administration of a telomere-targeting agent. Citation Format: Ann Marie Flusche, Jerry Shay, Ilgen Mender Ogunrinde. Enhancing adaptive immune responses with telomerase-mediated telomere targeting therapeutics in hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4143.