Chen Taoyong, Guo Jun, Yang Mingjin, Zhu Xuhui, Cao Xuetao
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
J Immunol. 2011 Feb 15;186(4):2219-28. doi: 10.4049/jimmunol.1002991. Epub 2011 Jan 17.
Exosomes derived from dendritic cells or tumor cells are a population of nanometer-sized membrane vesicles that can induce specific antitumor immunity. During investigation of the effects of hyperthermia on antitumor immune response, we found that exosomes derived from heat-stressed tumor cells (HS-TEX) could chemoattract and activate dendritic cells (DC) and T cells more potently than that by conventional tumor-derived exosomes. We show that HS-TEX contain chemokines, such as CCL2, CCL3, CCL4, CCL5, and CCL20, and the chemokine-containing HS-TEX are functionally competent in chemoattracting CD11c(+) DC and CD4(+)/CD8(+) T cells both in vitro and in vivo. Moreover, the production of chemokine-containing HS-TEX could be inhibited by ATP inhibitor, calcium chelator, and cholesterol scavenger, indicating that the mobilization of chemokines into exosomes was ATP- and calcium-dependent and via a lipid raft-dependent pathway. We consistently found that the intracellular chemokines could be enriched in lipid rafts after heat stress. Accordingly, intratumoral injection of HS-TEX could induce specific antitumor immune response more efficiently than that by tumor-derived exosomes, thus inhibiting tumor growth and prolonging survival of tumor-bearing mice more significantly. Therefore, our results demonstrate that exosomes derived from HS-TEX represent a kind of efficient tumor vaccine and can chemoattract and activate DC and T cells, inducing more potent antitumor immune response. Release of chemokines through exosomes via lipid raft-dependent pathway may be a new method of chemokine exocytosis.
源自树突状细胞或肿瘤细胞的外泌体是一群纳米级的膜泡，能够诱导特异性抗肿瘤免疫。在研究热疗对抗肿瘤免疫反应的影响过程中，我们发现热应激肿瘤细胞来源的外泌体（HS-TEX）比传统肿瘤来源的外泌体更能有效地趋化和激活树突状细胞（DC）和T细胞。我们发现HS-TEX含有趋化因子，如CCL2、CCL3、CCL4、CCL5和CCL20，并且含有趋化因子的HS-TEX在体外和体内对趋化CD11c(+) DC和CD4(+)/CD8(+) T细胞均具有功能活性。此外，ATP抑制剂、钙螯合剂和胆固醇清除剂可抑制含趋化因子的HS-TEX的产生，这表明趋化因子向外泌体中的转运是ATP和钙依赖性的，并且是通过脂筏依赖性途径。我们一致发现热应激后细胞内趋化因子可在脂筏中富集。因此，瘤内注射HS-TEX比肿瘤来源的外泌体更能有效地诱导特异性抗肿瘤免疫反应，从而更显著地抑制肿瘤生长并延长荷瘤小鼠的生存期。因此，我们的结果表明，HS-TEX来源的外泌体代表了一种有效的肿瘤疫苗，能够趋化和激活DC和T细胞，诱导更强的抗肿瘤免疫反应。通过脂筏依赖性途径经外泌体释放趋化因子可能是趋化因子胞吐的一种新方式。
