HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice
HSP110-HER2/neu chaperone complex vaccine induces protective immunity against spontaneous mammary tumors in HER-2/neu transgenic mice
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DOI：
10.4049/jimmunol.171.8.4054
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发表时间：
2003-10-15
影响因子：
4.4
通讯作者：
Subjeck, JR
中科院分区：
文献类型：
--
作者：
Manjili, MH;Wang, XY;Subjeck, JR
热休克蛋白（HSPs）被证明是强免疫佐剂，可引发针对癌症的先天和适应性免疫反应。HSP110在序列上与HSP70相关，与HSP70相比，与变性蛋白底物的结合和稳定效率提高了4倍。在本研究中，我们评估了HSP110与人HER-2/neu细胞内结构域（ICD）的热休克复合物在FVB-neu （FVBN202）转基因小鼠中引发有效的抗肿瘤免疫反应和抑制自发性乳腺肿瘤的能力。HSP110-ICD复合物能够打破对大鼠新蛋白的耐受性，抑制自发性乳腺肿瘤的发展。该疫苗诱导了icd特异性ifn - γ和IL-4的产生。耗竭研究表明，CD8(+) T细胞参与保护小鼠乳腺肿瘤免受攻击，而CD4(+) T细胞显示部分保护。免疫后无瘤动物血清IgG2a抗体滴度升高，荷瘤动物PBL中CD4(+)CD25（+）调节性T细胞升高，提示ifn - γ产生的Th1细胞可能部分保护CD4(+) T细胞抵抗乳腺肿瘤侵袭，而CD4(+)CD25（+）调节性X细胞（Th2细胞）可能抑制抗肿瘤免疫应答。综上所述，这些结果表明HSP110-ICD复合物可以诱导有效的产生ifn - γ的T细胞对抗自发性乳腺肿瘤，并且CD4(+) CD25（+）调节性T细胞的上调可能阻止免疫治疗后肿瘤的完全根除。
Heat shock proteins (HSPs) are shown to be strong immunoadjuvants, eliciting both innate and adaptive immune responses against cancers. HSP110 is related in sequence to HSP70 and is similar to4-fold more efficient in binding to and stabilizing denatured protein substrates compared with HSP70. In the present study we evaluated the ability of a heat shock complex of HSP110 with the intracellular domain (ICD) of human HER-2/neu to elicit effective antitumor immune responses and to inhibit spontaneous mammary tumors in FVB-neu (FVBN202) transgenic mice. The HSP110-ICD complex was capable of breaking tolerance against the rat neu protein and inhibiting spontaneous mammary tumor development. This vaccine induced ICD-specific IFN-gamma and IL-4 production. Depletion studies revealed that CD8(+) T cells were involved in protection against challenge with mouse mammary tumors, whereas CD4(+) T cells revealed partial protection. Increased IgG2a Ab titer in the sera of tumor-free animals after vaccination and elevated CD4(+) CD25(+) regulatory T cells in the PBL of tumor-bearing animals suggested that IFN-gamma-producing Th1 cells may be responsible for partial protection of CD4(+) T cells against the mammary tumor challenge, whereas CD4(+)CD25(+) regulatory X cells (Th2 cells) may suppress the antitumor immune responses. Together, these results suggest that HSP110-ICD complex can elicit effective IFN-gamma-producing T cells against spontaneous mammary tumors and that up-regulation of CD4(+) CD25(+) regulatory T cells may prevent complete eradication of the tumor following inummotherapy.