Department of Nanomedicine and Biopharmaceuticals, College of Life Science and Technology, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan, Hubei 430074, China.
J Adv Res. 2021 Mar 9;35:259-266. doi: 10.1016/j.jare.2021.03.003. eCollection 2022 Jan.
Cancer cells induced into immunogenic cell death (ICD) in vitro can be directly used as a whole cell vaccine for tumor immunotherapy with many advantages, especially enacting immediate and intense 'eat me' signals to engage immune system. Unfortunately, there have been few successes with in vitro ICD cancer cells as a treatment vaccine.
To demonstrate that cancer cells treated in vitro with a new class of potent ICD inducer, naphthylquinoxaline thymidine conjugate (NAP) followed by UVA irradiation would be able to act as an effective tumor immunotherapy directly.
The therapeutic potentials of treated cancer cell plus different vaccine adjuvants were assessed by in vivo liver tumor model and in vitro mixed lymphocyte reaction studies. The elicited activated T cells were determined with immunohistochemistry and T cell induced cytotoxicity studies.
Treatment of established H22 tumor with in vitro NAP and UVA treated cancer cell vaccine led to significantly improved survival. Further mixed lymphocyte reaction study implied that adjuvants alum and CpG would improve the therapeutic potential whereas poly IC would not be as effective. Subsequent in vivo validation of alum and CpG adjuvants indicated that only CpG in NAP and UVA treated cell vaccine resulted in markedly enhanced survival (median at 71 days and 50% tumor-free) as compared with PBS group (14.5 days, 0%) and CpG alone (36 days, 0%). It was revealed that the enhanced efficacy by CpG was specific to NAP and UVA treated cells. Moreover, the effective tumor immunotherapy was achieved through the infiltration of active CD4 and CD8 T cells in tumors and acquisition of cancer cell-specific cytotoxic CD8 T cells.
In vitro NAP and UVA treated cancer cells plus CpG adjuvant are effective tumor therapeutic vaccines .
体外诱导的具有免疫原性细胞死亡（ICD）的癌细胞可直接作为肿瘤免疫治疗的全细胞疫苗，具有许多优势，尤其是能立即引发强烈的“吃我”信号，从而激活免疫系统。然而，将体外 ICD 癌细胞作为治疗性疫苗应用于临床的成功案例却寥寥无几。
证明经体外新型强效 ICD 诱导剂萘基醌吖啶胸苷偶联物（NAP）联合 UVA 照射处理的癌细胞可直接作为有效的肿瘤免疫治疗剂。
通过体内肝肿瘤模型和体外混合淋巴细胞反应研究评估经处理的癌细胞与不同疫苗佐剂联合应用的治疗潜力。通过免疫组织化学和 T 细胞诱导细胞毒性研究来确定所引发的活化 T 细胞。
NAP 和 UVA 处理的癌细胞疫苗治疗已建立的 H22 肿瘤可显著提高荷瘤小鼠的存活率。进一步的混合淋巴细胞反应研究表明，佐剂明矾和 CpG 可提高治疗潜力，而聚肌苷酸则效果不佳。随后对明矾和 CpG 佐剂进行体内验证表明，仅 NAP 和 UVA 处理的细胞疫苗中 CpG 可显著提高存活率（中位数为 71 天，无肿瘤率为 50%），与 PBS 组（14.5 天，无肿瘤率为 0%）和单独 CpG 组（36 天，无肿瘤率为 0%）相比具有明显改善。结果表明，CpG 的增强作用是 NAP 和 UVA 处理细胞所特有的。此外，有效的肿瘤免疫治疗是通过肿瘤内浸润的活性 CD4 和 CD8 T 细胞以及获得的针对癌细胞的特异性细胞毒性 CD8 T 细胞实现的。
体外 NAP 和 UVA 处理的癌细胞加 CpG 佐剂是有效的肿瘤治疗性疫苗。
