期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 70, 期 5, 页码 1405-1417出版社
SPRINGER
DOI: 10.1007/s00262-020-02774-7
关键词
Oncolytic adenovirus; hTERT; Immunogenic cell death; ATP; CD8
资金
- Ministry of Education, Science, and Culture, Japan [16H05416, 19H03731, 25293323, 16K10862, 15K10446, 18K15242, 16K10596, 19K16835]
- Grants-in-Aid for Scientific Research [25293323, 15K10446, 16K10596, 16K10862, 19K16835, 19H03731, 16H05416, 18K15242] Funding Source: KAKEN
Study indicates that telomerase-specific oncolytic virotherapy is a promising strategy to enhance the efficacy of PD-1 blockade in osteosarcoma.
Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins alpha v beta 3 and alpha v beta 5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins alpha v beta 3 and alpha v beta 5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+ T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.
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