Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine.
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.
National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Taoyong
T
Chen
Jun
J
Guo
Mingjin
M
Yang
Xuhui
X
Zhu
Xuetao
X
Cao
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018925:Chemokines / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D055354:Exosomes / Q000276:immunology / Q000378:metabolism*; D018882:Heat Stress Disorders / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006358:Hot Temperature; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D021962:Membrane Microdomains / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D019496:Cancer Vaccines; D018925:Chemokines