Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface-Associated Calreticulin
Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface-Associated Calreticulin
复制标题
DOI：
10.1158/0008-5472.can-14-2089
复制
发表时间：
2015-04-15
期刊：
影响因子：
11.2
通讯作者：
Agostinis, Patrizia
中科院分区：
文献类型：
--
作者：
Dudek-Peric, Aleksandra M.;Ferreira, Gabriela B.;Agostinis, Patrizia
全身化疗通常被认为是免疫抑制性的，但很明显，某些化疗药物会在垂死的癌细胞中引发免疫原性危险信号，从而激发保护性抗肿瘤免疫。在这项研究中，我们研究了用于黑色素瘤肢体灌注（Mel-ILP）的局部应用疗法（例如美法仑）是否会产生相关的免疫原性作用。在人类黑色素瘤活检中，Mel-ILP 治疗上调了 IL1B、IL8 和 IL6，这与其在患者局部血清中的释放相关。尽管体外马法兰诱导黑色素瘤细胞凋亡并没有引起与危险信号相关的内质网和活性氧应激的阈值水平，例如细胞表面钙网蛋白的诱导，但预防性免疫和T细胞耗竭实验表明，体内施用马法兰可以刺激CD8+T细胞依赖性保护性抗肿瘤反应。有趣的是，与外源性钙网蛋白联合使用会增强疫苗接种效果，但与肿瘤坏死因子（一种经常与 Mel-ILP 联合使用的细胞因子）联合使用时，疫苗接种效果不会增强。我们的结果说明了马法兰如何引发炎症细胞死亡，而炎症细胞死亡可以通过危险信号钙网蛋白等免疫调节剂加以利用。 (C) 2015 AACR
Systemic chemotherapy generally has been considered immunosuppressive, but it has become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells that can incite protective antitumor immunity. In this study, we investigated whether locoregionally applied therapies, such as melphalan, used in limb perfusion for melanoma (Mel-ILP) produce related immunogenic effects. In human melanoma biopsies, Mel-ILP treatment upregulated IL1B, IL8, and IL6 associated with their release in patients' locoregional sera. Although induction of apoptosis in melanoma cells by melphalan in vitro did not elicit threshold levels of endoplasmic reticulum and reactive oxygen species stress associated with danger signals, such as induction of cell-surface calreticulin, prophylactic immunization and T-cell depletion experiments showed that melphalan administration in vivo could stimulate a CD8(+) T cell-dependent protective antitumor response. Interestingly, the vaccination effect was potentiated in combination with exogenous calreticulin, but not tumor necrosis factor, a cytokine often combined with Mel-ILP. Our results illustrate how melphalan triggers inflammatory cell death that can be leveraged by immunomodulators such as the danger signal calreticulin. (C) 2015 AACR