CD4(+) helper T cells are critical for protective immune responses and yet suboptimally primed in response to tumors. Cell-based vaccination strategies are under evaluation in clinical trials but limited by the need to derive antigen-presenting cells (APC) from patients or compatible healthy donors. To overcome these limitations, we developed CD4(+) T cell-targeted synthetic microbead-based artificial APC (aAPC) and used them to activate CD4(+) T lymphocytes specific for a tumor-associated model antigen (Ag) directly from the naive repertoire. In vitro, aAPC specifically primed Ag-specific CD4(+) T cells that were activated to express high levels of CD44, produced mainly interleukin 2, and could differentiate into Th1-like or Th2-like cells in combination with polarizing cytokines. I.v. administration of aAPC led to Ag-specific CD4(+) T-cell activation and proliferation in secondary lymphoid organs, conferred partial protection against subcutaneous tumors, and prevented the establishment of lung metastasis. Taken together, our data support the use of cell-free, synthetic aAPC as a specific and versatile alternative to expand peptide-specific CD4(+) T cells in adoptive and active immunotherapy.

译文

CD4(+) 辅助性T细胞对保护性免疫反应至关重要,但对肿瘤的反应却不是最佳的。基于细胞的疫苗接种策略正在临床试验中进行评估,但由于需要从患者或相容的健康供体获得抗原呈递细胞 (APC) 的限制。为了克服这些局限性,我们开发了基于CD4 () T细胞靶向的基于合成微珠的人工APC (aAPC),并使用它们直接从原始库中激活针对肿瘤相关模型抗原 (Ag) 的CD4 () T淋巴细胞。在体外,aAPC特异性引发Ag特异性CD4(+) T细胞,其被激活以表达高水平的CD44,主要产生白介素2,并且可以与极化细胞因子结合分化为Th1-like或Th2-like细胞。I.静脉给药aAPC导致Ag特异性CD4 () T细胞在次级淋巴器官中活化和增殖,对皮下肿瘤提供了部分保护,并阻止了肺转移的建立。综上所述,我们的数据支持使用无细胞,合成的aAPC作为一种特异性和多功能的替代品,以在过继和主动免疫疗法中扩展肽特异性CD4 () T细胞。

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