Department of Pediatrics, Section of Hematology-Oncology, Medical College of Wisconsin 53226, USA.
J Immunother. 2013 Jan;36(1):41-51. doi: 10.1097/CJI.0b013e318274590e.
When tumor vaccines are administered as cancer immunotherapy, cellular interactions at the vaccine site are crucial to the generation of antitumor immunity. Examining interactions at the vaccine site could provide important insights to the success or failure of vaccination. Our laboratory previously showed that while administration of a cell-based vaccine to tumor-free mice leads to productive antineuroblastoma immunity, vaccination of tumor-bearing mice does not. The goal of this study was to examine immune effectors at the vaccine site to identify mechanisms responsible for the generation of ineffective antitumor immunity in tumor-bearing mice. The results of this study show that vaccine sites of tumor-bearing mice contained significantly fewer T cells than vaccine sites of tumor-free mice. Similar migration and proliferation of T cells was observed in the vaccine sites of tumor-bearing and tumor-free mice, but T cells in the sites of tumor-bearing mice were more apoptotic. T cells at the vaccine sites of both tumor-free and tumor-bearing mice had an effector-memory phenotype and expressed activation markers. Despite the activated phenotype, T cells from tumor-bearing mice elicited defective antitumor immune responses. Although T cells from vaccine sites of tumor-bearing mice were capable of producing inflammatory cytokines, the T cells from tumor-bearing mice produced lower levels of cytokines compared with T cells from the tumor-free mice. Remarkably, this defect seems to be systemic, affecting distal T cells in tumor-bearing mice. This study demonstrates that the defective vaccine-induced immune response to neuroblastoma in tumor-bearing hosts originates as a result of tumor burden, resulting in poor antitumor immunity.
当肿瘤疫苗作为癌症免疫疗法被应用时，疫苗部位的细胞相互作用对产生抗肿瘤免疫至关重要。研究疫苗部位的相互作用可以为疫苗接种的成功或失败提供重要的见解。我们实验室之前的研究表明，虽然将细胞疫苗施用于无肿瘤的小鼠会导致有效的抗神经母细胞瘤免疫，但在荷瘤小鼠中接种疫苗则不会。本研究的目的是研究疫苗部位的免疫效应器，以确定导致荷瘤小鼠产生无效抗肿瘤免疫的机制。本研究的结果表明，荷瘤小鼠的疫苗部位所含的 T 细胞明显少于无肿瘤小鼠的疫苗部位。在荷瘤和无肿瘤小鼠的疫苗部位观察到 T 细胞的类似迁移和增殖，但荷瘤小鼠的 T 细胞凋亡更多。来自无肿瘤和荷瘤小鼠疫苗部位的 T 细胞具有效应记忆表型，并表达激活标志物。尽管存在激活表型，但来自荷瘤小鼠的 T 细胞引发了有缺陷的抗肿瘤免疫反应。尽管来自荷瘤小鼠疫苗部位的 T 细胞能够产生炎症细胞因子，但与无肿瘤小鼠的 T 细胞相比，荷瘤小鼠的 T 细胞产生的细胞因子水平较低。值得注意的是，这种缺陷似乎是全身性的，影响荷瘤小鼠的远端 T 细胞。本研究表明，荷瘤宿主中肿瘤负担导致的神经母细胞瘤疫苗诱导的免疫应答缺陷导致抗肿瘤免疫能力低下。
