Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, South Korea.
Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, South Korea.
Oncoimmunology. 2022 Jan 20;11(1):2023340. doi: 10.1080/2162402X.2021.2023340. eCollection 2022.
For clinical application by dendritic cell (DC)-based cancer immunotherapy, a proper adjuvant system to elicit a strong anticancer immune response is needed. Here, we investigated the potential of chorismate mutase (TBCM, Rv1885c), a putative (TB) virulence factor, as an immunoadjuvant in DC-based tumor immunotherapy. First, we found that TBCM functionally activated DCs by upregulating costimulatory molecules, increasing the secretion of proinflammatory cytokines, enhancing migration and inducing the Th1-type immune response in a dose-dependent manner via TLR4-mediated signaling. In addition, subcutaneous injection of TBCM-activated DCs loaded with cell lysates led to reduced tumor mass, enhanced mouse survival and lowered tumor incidence in lung carcinoma (LLC) cell-bearing mice. This is mainly mediated by functional cytotoxic T lymphocyte-mediated oncolytic activity and inhibition of cancer proliferation- and metastasis-related genes. Moreover, TBCM-induced DCs can also generate memory CD4 T cells and exert long-term tumor prevention effects. In conclusion, our findings suggest that TBCM (Rv1885c), a novel TLR4 agonist, could be used as an immunoadjuvant for DC-based cancer immunotherapy.
为了将树突状细胞（DC）为基础的癌症免疫疗法应用于临床，需要一种适当的佐剂系统来引发强烈的抗癌免疫反应。在这里，我们研究了色氨酸酶（TBCM，Rv1885c）作为基于 DC 的肿瘤免疫治疗中的免疫佐剂的潜力，色氨酸酶是一种假定的（TB）毒力因子。首先，我们发现 TBCM 通过 TLR4 介导的信号转导，以剂量依赖的方式功能性地激活 DC，上调共刺激分子，增加促炎细胞因子的分泌，增强迁移并诱导 Th1 型免疫反应。此外，皮下注射负载细胞裂解物的 TBCM 激活的 DC 可减少肿瘤体积、提高荷肺癌（LLC）细胞小鼠的存活率并降低肿瘤发生率。这主要是通过功能性细胞毒性 T 淋巴细胞介导的溶瘤活性和抑制癌症增殖和转移相关基因来介导的。此外，TBCM 诱导的 DC 还可以产生记忆 CD4 T 细胞并发挥长期的肿瘤预防作用。总之，我们的研究结果表明，新型 TLR4 激动剂 TBCM（Rv1885c）可作为基于 DC 的癌症免疫治疗的免疫佐剂。
