Department of Cancer Vaccine, Mie University Graduate School of Medicine, Mie, Japan.
J Immunol. 2010 Sep 15;185(6):3768-76. doi: 10.4049/jimmunol.0903649. Epub 2010 Aug 23.
CD8(+) CTLs play a critical role in antitumor immunity. However, vaccination with synthetic peptide containing CTL epitopes has not been generally effective in inducing protective antitumor immunity. In this study, we addressed the detailed mechanism(s) involved in this failure using a new tumor model of BALB/c transplanted tumors expressing NY-ESO-1, an extensively studied human cancer/testis Ag. Whereas peptide immunization with an H2-D(d)-restricted CTL epitope derived from NY-ESO-1 (NY-ESO-1 p81-88) induced NY-ESO-1(81-88)-specific CD8(+) T cells in draining lymph nodes and spleens, tumor growth was significantly enhanced. Single-cell analysis of specific CD8(+) T cells revealed that peptide immunization caused apoptosis of >80% of NY-ESO-1(81-88)-specific CD8(+) T cells at tumor sites and repetitive immunization further diminished the number of specific CD8(+) T cells. This phenomenon was associated with elevated surface expression of Fas and programmed death-1. When peptide vaccination was combined with an adjuvant, a TLR9 ligand CpG, the elevated Fas and programmed death-1 expression and apoptosis induction were not observed, and vaccine with peptide and CpG was associated with strong tumor growth inhibition. Selection of appropriate adjuvants is essential for development of effective cancer vaccines, with protection of effector T cells from peptide vaccine-induced apoptosis being a prime objective.
CD8(+) CTLs 在抗肿瘤免疫中发挥着关键作用。然而，用包含 CTL 表位的合成肽进行疫苗接种，一般来说并不能有效地诱导保护性抗肿瘤免疫。在这项研究中，我们使用一种新的 BALB/c 移植肿瘤模型来研究这种失败的详细机制，该模型表达 NY-ESO-1，这是一种经过广泛研究的人类癌症/睾丸抗原。虽然用 H2-D(d) 限制性 CTL 表位（来自 NY-ESO-1 的 NY-ESO-1 p81-88）进行肽免疫接种会在引流淋巴结和脾脏中诱导 NY-ESO-1(81-88)-特异性 CD8(+) T 细胞，但肿瘤生长明显增强。特异性 CD8(+) T 细胞的单细胞分析显示，肽免疫接种会导致 >80%的 NY-ESO-1(81-88)-特异性 CD8(+) T 细胞在肿瘤部位发生凋亡，重复免疫接种进一步减少了特异性 CD8(+) T 细胞的数量。这种现象与 Fas 和程序性死亡-1 表面表达的增加有关。当肽疫苗接种与佐剂，即 TLR9 配体 CpG 联合使用时， Fas 和程序性死亡-1 的表达增加和凋亡诱导则不会发生，而含有肽和 CpG 的疫苗则与强烈的肿瘤生长抑制相关。选择合适的佐剂对于开发有效的癌症疫苗至关重要，保护效应 T 细胞免受肽疫苗诱导的凋亡是首要目标。
