Hu Che-Yuan, Hung Chi-Feng, Chen Pi-Che, Hsu Jia-Yu, Wang Chung-Teng, Lai Ming-Derg, Tsai Yuh-Shyan, Shiau Ai-Li, Shieh Gia-Shing, Wu Chao-Liang
Department of Urology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
Department of Urology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi City 60002, Taiwan.
Biomedicines. 2023 Sep 22;11(10):2598. doi: 10.3390/biomedicines11102598.
Immunotherapy has emerged as a promising modality for cancer treatment. Dendritic cell immunoreceptor (DCIR), a C-type lectin receptor, is expressed mainly by dendritic cells (DCs) and mediates inhibitory intracellular signaling. Inhibition of DCIR activation may enhance antitumor activity. DCIR is encoded by in humans and by in mice. Gene gun-mediated delivery of short hairpin RNA (shRNA) targeting into mice bearing bladder tumors reduces DCIR expression in DCs, inhibiting tumor growth and inducing CD8 T cell immune responses. Various oncolytic adenoviruses have been developed in clinical trials. Previously, we have developed Ad.LCY, an oncolytic adenovirus regulated by Oct4 and hypoxia, and demonstrated its antitumor efficacy. Here, we generated a shRNA-expressing oncolytic adenovirus derived from Ad.LCY, designated Ad.shDCIR, aimed at inducing more robust antitumor immune responses. Our results show that treatment with Ad.shDCIR reduced Clec4a expression in DCs in cell culture. Furthermore, Ad.shDCIR exerted cytolytic effects solely on MBT-2 bladder cancer cells but not on normal NIH 3T3 mouse fibroblasts, confirming the tumor selectivity of Ad.shDCIR. Compared to Ad.LCY, Ad.shDCIR induced higher cytotoxic T lymphocyte (CTL) activity in MBT-2 tumor-bearing immunocompetent mice. In addition, Ad.shDCIR and Ad.LCY exhibited similar antitumor effects on inhibiting tumor growth. Notably, Ad.shDCIR was superior to Ad.LCY in prolonging the survival of tumor-bearing mice. In conclusion, Ad.shDCIR may be further explored as a combination therapy of virotherapy and immunotherapy for bladder cancer and likely other types of cancer.
免疫疗法已成为一种很有前景的癌症治疗方式。树突状细胞免疫受体（DCIR）是一种C型凝集素受体，主要由树突状细胞（DC）表达，并介导抑制性细胞内信号传导。抑制DCIR激活可能增强抗肿瘤活性。DCIR在人类中由[具体基因名称1]编码，在小鼠中由[具体基因名称2]编码。基因枪介导的将靶向[具体基因名称1]的短发夹RNA（shRNA）递送至携带膀胱肿瘤的小鼠体内，可降低DC中DCIR的表达，抑制肿瘤生长并诱导CD8 T细胞免疫反应。各种溶瘤腺病毒已在临床试验中得到开发。此前，我们开发了由Oct4和缺氧调节的溶瘤腺病毒Ad.LCY，并证明了其抗肿瘤功效。在此，我们构建了一种源自Ad.LCY的表达shRNA的溶瘤腺病毒，命名为Ad.shDCIR，旨在诱导更强有力的抗肿瘤免疫反应。我们的结果表明，在细胞培养中，用Ad.shDCIR处理可降低DC中Clec4a的表达。此外，Ad.shDCIR仅对MBT - 2膀胱癌细胞发挥溶细胞作用，而对正常的NIH 3T3小鼠成纤维细胞无作用，证实了Ad.shDCIR的肿瘤选择性。与Ad.LCY相比，Ad.shDCIR在携带MBT - 2肿瘤的免疫健全小鼠中诱导了更高的细胞毒性T淋巴细胞（CTL）活性。此外，Ad.shDCIR和Ad.LCY在抑制肿瘤生长方面表现出相似的抗肿瘤效果。值得注意的是，在延长荷瘤小鼠的生存期方面，Ad.shDCIR优于Ad.LCY。总之，Ad.shDCIR可作为膀胱癌以及可能其他类型癌症的病毒疗法和免疫疗法联合治疗的进一步探索对象。
