Immunogenic death of colon cancer cells treated with oxaliplatin
Immunogenic death of colon cancer cells treated with oxaliplatin
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DOI：
10.1038/onc.2009.356
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发表时间：
2010-01-01
期刊：
影响因子：
8
通讯作者：
Kroemer, G.
中科院分区：
文献类型：
--
作者：
Tesniere, A.;Schlemmer, F.;Kroemer, G.
钙网蛋白（CRT）的凋亡前暴露和高迁移率族蛋白1（HMGB 1）的凋亡后释放都是蒽环类抗生素引起的免疫原性细胞死亡所必需的。在这里，我们表明奥沙利铂（OXP）和顺铂（CDDP）在触发HMGB 1释放方面同样有效。然而，OXP，而不是CDDP，刺激细胞凋亡前CRT暴露在一系列的小鼠和人结肠癌细胞系。皮下注射OXP处理的结直肠癌（CRC），CT 26，细胞诱导的抗癌免疫反应，减少了短干扰RNA介导的CRT或HMGB 1的消耗。相反，CDDP处理的CT 26细胞未能诱导抗癌免疫，除非重组CRT蛋白被吸收到细胞中。植入免疫活性小鼠的CT 26肿瘤对体内OXP治疗有反应，当CT 26细胞的CRT暴露被抑制或当CT 26细胞植入免疫缺陷小鼠时，这种治疗反应消失。敲除Toll样受体4（TLR 4）（HMGB 1的受体）也导致针对OXP处理的CT 26细胞的免疫应答缺陷。在接受基于OXP的化疗方案的晚期（IV期，杜克D）CRC患者中，TLR 4的功能丧失等位基因（Asp 299 Gly与Thr 399 Ile连锁不平衡，降低其对HMGB 1的亲和力）与一般人群一样普遍。然而，与携带正常TLR 4等位基因的患者相比，携带TLR 4功能丧失等位基因的患者表现出降低的无进展生存期和总生存期。总之，OXP诱导CRC细胞的免疫原性死亡，这种作用决定了其在CRC患者中的治疗效果。Oncogene（2010）29，482-491; doi：10.1038/onc.2009.356; 2009年11月2日在线发表
Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNA-mediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients. Oncogene (2010) 29, 482-491; doi: 10.1038/onc.2009.356; published online 2 November 2009