Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells
Severe, but not mild heat-shock treatment induces immunogenic cell death in cancer cells
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DOI：
10.1080/2162402x.2017.1311433
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Spisek, Radek
中科院分区：
文献类型：
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作者：
Adkins, Irena;Sadilkova, Lenka;Spisek, Radek
肿瘤细胞的轻度热休克（mHS）治疗< 42 ℃的免疫原性机制主要归因于热休克蛋白的作用;然而，对于经历严重细胞毒性热休克治疗（sHS > 43 ℃）的肿瘤细胞的免疫原性知之甚少。在这里，我们发现sHS而不是mHS（42 ℃）诱导人癌细胞系中的免疫原性细胞死亡，如通过诱导ER应激反应和ROS产生、钙网蛋白、HSP 70和HSP 90的细胞表面暴露、细胞表面CD 47的减少、ATP和HMGB 1的释放所定义的。只有sHS处理的肿瘤细胞被有效地杀死和吞噬的树突状细胞（DC），这是部分依赖于细胞表面钙网蛋白。负载mHS或sHS处理的肿瘤细胞的DC显示出相似的成熟水平，并在体外刺激产生IFN g的CD 8（+）C T细胞，而无需任何额外的佐剂。然而，只有负载sHS处理的肿瘤细胞的DC刺激抗原特异性CD 4（+）T细胞，并诱导更高的CD 8（+）T细胞活化和增殖。sHS处理的鼠细胞也暴露钙网蛋白、HSP 70和HSP 90，并且比mHS处理的细胞活化更高的DC成熟。用经sHS处理的肿瘤细胞接种疫苗在小鼠中引起保护性免疫。在这项研究中，我们定义了sHS治疗人肺和卵巢肿瘤细胞的特定条件，以达到有效细胞死亡，免疫原性和免疫疫苗产生的肿瘤抗原含量之间的最佳比例。
The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42 degrees C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43 degrees C). Here, we found that sHS, but not mHS (42 degrees C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1. Only sHS-treated tumor cells were efficiently killed and phagocytosed by dendritic cells (DCs), which was partially dependent on cell surface calreticulin. DCs loaded with mHS or sHS-treated tumor cells displayed similar level of maturation and stimulated IFNg-producing CD8(+)C T cells without any additional adjuvants in vitro. However, only DCs loaded with sHS-treated tumor cells stimulated antigen-specific CD4(+) T cells and induced higher CD8(+) T-cell activation and proliferation. sHS-treated murine cells also exposed calreticulin, HSP70 and HSP90 and activated higher DC maturation than mHS treated cells. Vaccination with sHS-treated tumor cells elicited protective immunity in mice. In this study, we defined specific conditions for the sHS treatment of human lung and ovarian tumor cells to arrive at optimal ratio between effective cell death, immunogenicity and content of tumor antigens for immunotherapeutic vaccine generation.