Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice
Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice
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DOI：
10.1172/jci40269
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发表时间：
2010-04-01
影响因子：
15.9
通讯作者：
Gabrilovich, Dmitry I.
中科院分区：
文献类型：
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作者：
Ramakrishnan, Rupal;Assudani, Deepak;Gabrilovich, Dmitry I.
由于临床疗效较低，肿瘤免疫治疗面临严峻挑战。最近，一些临床研究报告称，在不同类型的癌症患者中，癌症疫苗与化疗联合使用时，偶然发现客观的临床反应率很高。然而，这一现象的发生机制尚不清楚。在这里，我们在小鼠身上测试了几种癌症疫苗，以及一种过继的T细胞转移方法，将其与几种广泛使用的化疗药物结合起来进行癌症免疫治疗。我们发现，化疗通过CTL释放的穿孔素非依赖性增加对GrzB的通透性，使肿瘤细胞更容易受到CTL的细胞毒作用的影响。这种作用是通过上调肿瘤细胞表面甘露糖-6-磷酸受体介导的，并在小鼠和人类细胞中观察到。当与化疗结合时，针对特定抗原而产生的CTL能够诱导不表达这些抗原的邻近肿瘤细胞发生凋亡。这些数据表明，当与化疗相结合时，少量的CTL可以发挥强大的抗肿瘤作用。此外，这些结果为将这些方法结合用于晚期癌症患者的治疗提供了强有力的理由。
Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear. Here, we tested in mice several cancer vaccines and an adoptive T cell transfer approach to cancer immunotherapy in combination with several widely used chemotherapeutic drugs. We found that chemotherapy made tumor cells more susceptible to the cytotoxic effect of CTLs through a dramatic perforin-independent increase in permeability to GrzB released by the CTLs. This effect was mediated via upregulation of mannose-6-phosphate receptors on the surface of tumor cells and was observed in mouse and human cells. When combined with chemotherapy, CTLs raised against specific antigens were able to induce apoptosis in neighboring tumor cells that did not express those antigens. These data suggest that small numbers of CTLs could mediate a potent antitumor effect when combined with chemotherapy. In addition, these results provide a strong rationale for combining these modalities for the treatment of patients with advanced cancers.