The DAMP Laboratory, Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Autophagy. 2012 Aug;8(8):1264-6. doi: 10.4161/auto.20752. Epub 2012 Jun 4.
Cancer is the leading cause of death in the United States in those dying under the age of 85. Although cancer is increasingly controlled as a chronic disease, true cures of patients with metastatic epithelial malignancies have rarely been obtained with currently available systemic therapies. For example, administration of high-dose recombinant interleukin 2 (IL2), enhancing cytolytic immune cell proliferation and delivery, promotes complete antitumor responses in < 10% of treated individuals. Means to reduce the toxicity, attributed to a cytokine storm and an associated "systemic autophagic syndrome" as well as enhance efficacy and increase the potential set of malignancies in which it is applied (currently patients with renal cancer and melanoma) would be of great interest. IL2 promotes both T-cell and NK cell induction of immune cell-mediated autophagy (iC-MA) in tumor targets. We have demonstrated that HMGB1 is detected at high levels in the serum of IL2-treated mice with translocation to the cytoplasm from the nucleus in the liver, consistent with HMGB1's release in response to stress, and ability to sustain autophagy. Limiting autophagy in mice with coadministration of chloroquine (CQ) diminishes serum levels of HMGB1, cytokines (IFNG and IL6 but not IL18), and autophagic flux, attenuating weight gain, enhancing DC, T-cell and NK cell numbers, and promoting long-term tumor control in a murine hepatic metastases model. Autophagy (programmed cell survival) is a metabolic process associated with promotion of late cancer growth. In tumor cell lines, CQ treatment limits ATP production through inhibition of oxidative phosphorylation and promotion of apoptosis. CQ increases autophagic vacuoles and LC3-II levels in tumor cells, associated with increased annexin V(+)/PI(-) cells, cleaved-PARP, cleaved-CASP3, and cytochrome c release from mitochondria. These observations, limiting toxicity and prolonging antitumor effects, with a combination of IL2 and autophagy inhibition in murine models are now being tested by the Cytokine Working Group in patients with advanced renal cell carcinoma.
癌症是美国 85 岁以下死亡人群的主要死因。尽管癌症作为一种慢性病越来越得到控制，但目前可用的系统疗法很少能真正治愈转移性上皮恶性肿瘤患者。例如，高剂量重组白细胞介素 2（IL2）的给药，增强细胞溶解性免疫细胞的增殖和传递，在接受治疗的个体中 <10%的个体中促进完全抗肿瘤反应。减少毒性的方法，归因于细胞因子风暴和相关的“全身自噬综合征”，以及增强疗效并增加其应用的潜在恶性肿瘤范围（目前是肾癌和黑色素瘤患者）将非常有趣。IL2 促进 T 细胞和 NK 细胞诱导肿瘤靶标中的免疫细胞介导的自噬（iC-MA）。我们已经证明，HMGB1 在接受 IL2 治疗的小鼠血清中高水平检测到，从肝脏的核内易位到细胞质，与 HMGB1 对压力的释放以及维持自噬的能力一致。在用氯喹（CQ）共同给药限制自噬时，减少了血清中 HMGB1、细胞因子（IFNG 和 IL6 但不是 IL18）和自噬通量的水平，减轻了体重增加，增强了 DC、T 细胞和 NK 细胞的数量，并促进了小鼠肝转移模型中的长期肿瘤控制。自噬（程序性细胞存活）是与促进晚期癌症生长相关的代谢过程。在肿瘤细胞系中，CQ 通过抑制氧化磷酸化和促进细胞凋亡来限制 ATP 的产生。CQ 增加肿瘤细胞中的自噬空泡和 LC3-II 水平，与 Annexin V(+)/PI(-)细胞、cleaved-PARP、cleaved-CASP3 和细胞色素 c 从线粒体释放增加相关。这些观察结果，通过在小鼠模型中限制 IL2 和自噬抑制的毒性并延长抗肿瘤作用，目前正在由细胞因子工作组在晚期肾癌患者中进行测试。
