title: Adenovirus expressing both thymidine kinase and soluble PD1 enhances antitumor immunity by strengthening CD8 T-cell response.
abstract: Adenoviruses harboring the herpes simplex virus thymidine kinase (HSVtk) gene under the regulation of a trans-splicing ribozyme targeting human telomerase reverse transcriptase (hTERT-TR) show marked and specific antitumor activity. In addition to inducing tumor cell death by direct cytotoxicity, it is becoming clear that HSVtk also induces antitumor immunity. Programmed death ligand 1 (PD-L1) expressed on tumor cell surfaces mediates tumor-induced immunoresistance by inhibiting PD1-expressing tumor-infiltrating T cells. Here, we explored whether a soluble form of PD1 (sPD1-Ig), which blocks PD-L1, could synergize with TERT-TR-regulated HSVtk to enhance the adenoviral therapeutic efficacy by boosting antitumor immunity. Tumor antigen released by HSVtk-transduced tumors successfully primed tumor antigen-specific CD8 T cells via dendritic cells (DC). Regression of murine tumors was markedly enhanced when sPD1-Ig was incorporated into the adenovirus as compared with a single-module adenovirus expressing only HSVtk. This effect was abolished by CD8 T-cell depletion. Consistent with this, following adoptive transfer of tumor antigen-specific CD8 T cells into tumor-bearing Rag1(-/-) mice, dual-module adenovirus significantly enhanced CD8 T cell-mediated tumor rejection. In addition, secondary tumor challenge at a distal site was completely suppressed in mice treated with a dual-module adenovirus. These results suggest that a dual-targeting strategy to elicit both tumor antigen priming and tumor-induced immunoresistance enhances CD8 T cell-mediated antitumor immunity.
authors: Genitourinary Cancer Branch, Research Institute National Cancer Center, Gyeonggi-do, Korea.
authors: Seung-Pil
authors: SP
authors: Shin
authors: Hye-Hyun
authors: HH
authors: Seo
authors: Jae-Hun
authors: JH
authors: Shin
authors: Hyung-Bae
authors: HB
authors: Park
authors: Dong-Pyo
authors: DP
authors: Lim
authors: Hyeon-Seok
authors: HS
authors: Eom
authors: Yong-Soo
authors: YS
authors: Bae
authors: In-Hoo
authors: IH
authors: Kim
authors: Kyungho
authors: K
authors: Choi
authors: Sang-Jin
authors: SJ
authors: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D013937:Thymidine Kinase / Q000235:genetics* / Q000378:metabolism; D020040:Trans-Splicing
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D019496:Cancer Vaccines; D013937:Thymidine Kinase; C509186:TERT protein, human; D019098:Telomerase