Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity.
Combination therapy with cisplatin and anti-4-1BB: synergistic anticancer effects and amelioration of cisplatin-induced nephrotoxicity.
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DOI：
10.1158/0008-5472.can-08-1365
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发表时间：
2008-09-15
期刊：
影响因子：
11.2
通讯作者：
Kwon BS
中科院分区：
文献类型：
--
作者：
Kim YH;Choi BK;Kim KH;Kang SW;Kwon BS
抗4-1BB和顺铂在CT-26结肠癌模型中显示出协同抗癌作用，在预防性或治疗性处理的>60%的小鼠中产生完全消退。无瘤小鼠形成了持久的CD 8 + T依赖性肿瘤特异性记忆。抗4-1BB可诱导T和B细胞从顺铂介导的淋巴细胞减少症中快速再增殖，并诱导IFN-γ+ CD 11 c + CD 8 + T细胞分化和扩增。顺铂促进幼稚、效应和记忆CD 8 + T细胞的扩增;联合治疗产生的淋巴细胞几乎是单用抗4-1BB的两倍。顺铂增加抗原致敏的T细胞上的4-1BB，并诱导肾小管上皮细胞上的4-1BB从头产生。4-1BB的交联通过增加抗凋亡分子的表达来保护T细胞和肾上皮免于顺铂介导的凋亡。因此，顺铂诱导的4-1BB提供了改善顺铂治疗中固有的淋巴细胞减少症和肾毒性的机制。我们得出结论，抗4-1BB和顺铂的化学免疫治疗在肿瘤杀伤和预防器官特异性毒性方面具有协同作用。
Anti-4-1BB and cisplatin showed synergistic anti-cancer effects in the CT-26 colon carcinoma model, producing complete regression in >60% of mice with either preventive or therapeutic treatment. The tumor-free mice formed long-lasting CD8+ T-dependent tumor-specific memory. Anti-4-1BB induced rapid repopulation of T and B cells from cisplatin-mediated lymphopenia and differentiation and expansion of IFN-γ+CD11c+CD8+ T cells. Cisplatin facilitated expansion of naïve, effector, and memory CD8+ T cells; combination therapy produced almost twice as many lymphoid cells as anti-4-1BB alone. Cisplatin increased 4-1BB on antigen-primed T cells and induced 4-1BB de novo on kidney tubular epithelium. Cross-linking of 4-1BB protected the T cells and kidney epithelium from cisplatin-mediated apoptosis by increasing expression of anti-apoptotic molecules. Thus cisplatin-induced 4-1BB provided a mechanism for amelioration of the lymphopenia and nephrotoxicity inherent in cisplatin treatment. We concluded that chemo-immunotherapy with anti-4-1BB and cisplatin is synergistic in tumor killing and prevention of organ-specific toxicity.