title: Low-dose cisplatin converts the tumor microenvironment into a permissive state for HSVtk-induced antitumor immunity in HPV16-related tonsillar carcinoma.
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.
authors.affiliation: Genitourinary Cancer Branch.
authors.forename: Ah Ra
authors.initials: AR
authors.lastname: Goh
authors.affiliation: Genitourinary Cancer Branch.
authors.forename: Seung-Pil
authors.initials: SP
authors.lastname: Shin
authors.affiliation: Genitourinary Cancer Branch.
authors.forename: Na-Rae
authors.initials: NR
authors.lastname: Jung
authors.affiliation: Specific Organs Cancer Branch, Department of Otolaryngology.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Ryu
authors.affiliation: Hematologic-Oncology, Research Institute & Hospital, National Cancer Center, Goyang, South Korea.
authors.forename: Hyeon Seok
authors.initials: HS
authors.lastname: Eom
authors.affiliation: Sanford Cancer Research Center, Sanford ENT - Head and Neck Surgery, Sioux Falls, South Dakota.
authors.forename: John H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Choi
authors.affiliation: Genitourinary Cancer Branch. Electronic address: leesj@ncc.re.kr.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Specific Organs Cancer Branch, Department of Otolaryngology. Electronic address: jysorl@ncc.re.kr.
authors.forename: Yuh-S
authors.initials: YS
authors.lastname: Jung
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000628:therapy* / Q000821:virology; D002453:Cell Cycle; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D052162:Human papillomavirus 16 / Q000472:pathogenicity; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D030361:Papillomavirus Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018139:Simplexvirus / Q000201:enzymology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014067:Tonsillar Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D012333:RNA, Messenger; D013937:Thymidine Kinase; D002945:Cisplatin
keywords: Chemotherapy; Cisplatin; Human papillomavirus; T cell; TERT-targeting ribozyme; Tonsil cancer