Low-dose cisplatin converts the tumor microenvironment into a permissive state for HSVtk-induced antitumor immunity in HPV16-related tonsillar carcinoma. Issue 2 (28th January 2015)

• Record Type: Journal Article
• Authors: Goh, Ah Ra; Shin, Seung-Pil; Jung, Na-Rae; Ryu, Chang-Hwan; Eom, Hyeon Seok; Lee, John H.; Choi, Kyungho; Lee, Sang-Jin; Jung, Yuh-S.
• Is Part Of: Cancer letters. Volume 356:Issue 2(2015)Part B
• Page Start: 743
• Page End: 750
• Publication Date: 2015-01-28
• Subjects: Cisplatin -- TERT-targeting ribozyme -- T cell -- Human papillomavirus -- Tonsil cancer -- Chemotherapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2014.10.022
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: An adenovirus harboring the HSV thymidine kinase (HSVtk) gene under the regulation of a trans -splicing ribozyme that targets telomerase is cytotoxic to cancer cells because it inhibits DNA replication (Ad5mTR). Furthermore, it induces anti-tumor immunity by activating cytotoxic T cells. Because multiple chemotherapeutic agents also activate cytotoxic T-cell immunity during the direct killing process of tumor cells, we herein explored whether low-dose cisplatin could synergize with cytotoxic Ad5mTR to potentiate its therapeutic effect by boosting anti-tumor immunity in a murine HPV16-associated tonsillar carcinoma model. Tumor regression was enhanced when low-dose (1 mg/kg) cisplatin was added to suicide gene therapy using Ad5mTR. Meanwhile, 1 mg/kg cisplatin alone had no tumor-suppressive effects and did not result in any systemic toxicity. Thus, cisplatin along with Ad5mTR improved tumor clearance by increasing the number of E7-specific CD8+ T cells. Specifically, analysis of the tumors and lymph nodes supported improved immune clearance by increasing the number of E7-specific CD8+ T cells inside tumors (40%, P < 0.05) as a result of the combination of suicide gene and cisplatin therapy. These results suggest that a low dose of cisplatin potentiates CD8+ T-cell-mediated anti-tumor immunity, and its addition to the HSVtk-based adenovirus results in additional therapeutic benefits for HPV16-positive head and neck cancer patients.