T-Cell Costimulation in the Design of Cancer Vaccines

癌症疫苗设计中的 T 细胞共刺激

• 批准号: 6559279
• 负责人: JEFFREY SCHLOM
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6559279
• 关键词: Poxviridae; T lymphocyte; antigen presenting cell; biological signal transduction; biotechnology; cytotoxic T lymphocyte; dendritic cells; drug design /synthesis /production; gene expression; laboratory mouse; leukocyte activation /transformation; neoplasm /cancer vaccine; neoplastic cell; transfection /expression vector; vaccine development; vaccinia virus; vector vaccine

The activation of T cells has been shown to require at least two signals via molecules present on professional antigen-presenting cells: signal 1 via a peptide/MHC complex, and signal 2 via a costimulatory molecule. Studies are being conducted on the impact of hyperexpression of multiple costimulatory molecules in the activation of T cells. Pox virus vectors (vaccinia and avipox) are being used because of their ability to efficiently express multiple transgenes. Murine tumor cells provided with signal 1 and infected with either recombinant vaccinia or avipox vectors containing a TRIad of COstimulatory Molecules (B7-1/ICAM-1/LFA-3, designated TRICOM) induce the activation of T cells to a far greater extent than cells infected with any one or two costimulatory molecules. Despite this T-cell "hyperstimulation" using TRICOM vectors, no evidence of apoptosis above that seen using the B7-1 vector was observed. Experiments using a four-gene construct have shown that TRICOM recombinants can enhance antigen-specific T-cell responses in vivo. Studies are also ongoing to determine if dendritic cells infected with these TRICOM vectors are rendered more efficient in enhancing T-cell responses. Peptide-pulsed dendritic cells infected with rF-TRICOM or rV-TRICOM induced cytotoxic T-lymphocyte activity in vitro and in vivo to a markedly greater extent than peptide-pulsed dendritic cells. These studies thus demonstrate the ability of vectors to introduce three costimulatory molecules into cells, thereby activating T-cell populations to levels far greater than those achieved with the use of one or two costimulatory molecules. This new threshold of T-cell activation in vaccine design is currently being studied.

T 细胞的激活已被证明需要至少两个通过专业抗原呈递细胞上存在的分子发出的信号：通过肽/MHC 复合物的信号 1，以及通过共刺激分子的信号 2。目前正在研究多种共刺激分子的超表达对 T 细胞激活的影响。痘病毒载体（痘苗病毒和禽痘病毒）因其能够有效表达多种转基因而被使用。提供信号 1 并用含有 TRIad 共刺激分子（B7-1/ICAM-1/LFA-3，命名为 TRICOM）的重组牛痘或禽痘载体感染的鼠肿瘤细胞诱导 T 细胞的激活程度远大于被任何一种或两种共刺激分子感染的细胞。尽管使用 TRICOM 载体对 T 细胞进行“过度刺激”，但没有观察到使用 B7-1 载体观察到的凋亡证据。使用四基因构建体的实验表明，TRICOM 重组体可以增强体内抗原特异性 T 细胞反应。研究还正在进行中，以确定感染这些 TRICOM 载体的树突状细胞是否能够更有效地增强 T 细胞反应。感染rF-TRICOM或rV-TRICOM的肽脉冲树突状细胞在体外和体内诱导细胞毒性T淋巴细胞活性的程度明显高于肽脉冲树突细胞。因此，这些研究证明了载体能够将三种共刺激分子引入细胞中，从而将T细胞群激活到远远高于使用一种或两种共刺激分子所达到的水平。目前正在研究疫苗设计中 T 细胞激活的新阈值。