Immune Mechanism of the Antitumor Effects Generated by Bortezomib
Immune Mechanism of the Antitumor Effects Generated by Bortezomib
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DOI：
10.4049/jimmunol.1103826
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发表时间：
2012-09-15
影响因子：
4.4
通讯作者：
Hung, Chien-Fu
中科院分区：
文献类型：
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作者：
Chang, Chih-Long;Hsu, Yun-Ting;Hung, Chien-Fu
硼替佐米是一种蛋白酶体抑制剂，是一种常用于治疗多种人类癌症的化疗药物。硼替佐米诱导的肿瘤细胞免疫原性的抗肿瘤作用尚未完全阐明。在这项研究中，我们研究了免疫介导的抗肿瘤作用的产生，在小鼠卵巢肿瘤模型中的硼替佐米治疗的反应。我们观察到用硼替佐米治疗的荷瘤小鼠具有CD 8（+）T细胞介导的肿瘤生长抑制。此外，从硼替佐米处理或未处理的肿瘤细胞产生的基于肿瘤细胞的疫苗的比较显示，用药物处理的基于肿瘤细胞的疫苗接种引起了有效的肿瘤特异性CD 8（+）T细胞免疫应答，在荷瘤小鼠中具有改善的治疗性抗肿瘤效果。相反，未处理的基于肿瘤细胞的疫苗没有引起明显的抗肿瘤反应。用硼替佐米处理肿瘤细胞导致细胞表面Hsp 60和Hsp 90的上调，并促进树突状细胞（DC）对它们的吞噬作用。然而，细胞表面Hsp 60的表达，而不是Hsp 90，是硼替佐米处理的肿瘤细胞是否能产生肿瘤特异性CD 8（+）T细胞的更重要的决定因素。在体外用硼替佐米处理的CD 11 c（+）DCs具有增强的吞噬活性。此外，硼替佐米治疗的荷瘤小鼠的CD 11 c（+）DC成熟增加。在较低浓度下，硼替佐米对T细胞增殖没有抑制作用。综上所述，我们的数据表明硼替佐米可以通过上调热休克蛋白60和热休克蛋白90的细胞表面表达来赋予肿瘤细胞免疫原性，以及改善DC功能，这导致有效的免疫介导的抗肿瘤作用。免疫学杂志，2012，189：3209-3220。
Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8(+) T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8(+) T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8(+) T cells. CD11c(+) DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c(+) DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation. Taken together, our data indicate that bortezomib can render tumor cells immunogenic by upregulating the cell surface expression of heat shock protein 60 and heat shock protein 90, as well as improve DC function, which results in potent immune-mediated antitumor effects. The Journal of Immunology, 2012, 189:3209-3220.