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More Efficient Induction of HLA-A*0201-Restricted and Carcinoembryonic Antigen (CEA)–Specific CTL Response by Immunization with Exosomes Prepared from Heat-Stressed CEA-Positive Tumor Cells

Authors' Affiliations: ¹ Institute of Immunology, Zhejiang University, Hangzhou, People's Republic of China and ² Institute of Immunology, Second Military Medical University, Shanghai, People's Republic of China

Requests for reprints: Xuetao Cao, Institute of Immunology, Zhejiang University, 353 Yanan Road, Hangzhou 310031, People's Republic of China. Fax: 86-571-8721-7329; E-mail: caoxt{at}public3.sta.net.cn.

Purpose: Tumor-derived exosomes are proposed as a new type of cancer vaccine. Heat shock proteins are potent Th1 adjuvant, and heat stress can induce heat shock protein and MHC-I expression in tumor cells, leading to the increased immunogenicity of tumor cells. To improve the immunogenicity of exosomes as cancer vaccine, we prepared exosomes from heat-stressed carcinoembryonic antigen (CEA)–positive tumor cells (CEA⁺/HS-Exo) and tested the efficacy of these exosomes in the induction of CEA-specific antitumor immunity.

Experimental Design: First, we identified the composition of CEA⁺/HS-Exo and observed their effects on human dendritic cell maturation. Then, we evaluated their ability to induce a CEA-specific immune response in vivo in HLA-A2.1/K^b transgenic mice and CEA-specific CTL response in vitro in HLA-A*0201⁺ healthy donors and HLA-A*0201⁺CEA⁺ cancer patients.

Results: CEA⁺/HS-Exo contained CEA and more heat shock protein 70 and MHC-I and significantly induced dendritic cell maturation. Immunization of HLA-A2.1/K^b transgenic mice with CEA⁺/HS-Exo was more efficient in priming a CEA-specific CTL, and the CTL showed antitumor effect when adoptively transferred to SW480-bearing nude mice. Moreover, in vitro incubation of lymphocytes from HLA-A*0201⁺ healthy donors and HLA-A*0201⁺CEA⁺ cancer patients with CEA⁺/HS-Exo-pulsed autologous dendritic cells induces HLA-A*0201-restricted and CEA-specific CTL response.

Conclusions: Our results show that CEA⁺/HS-Exo has superior immunogenicity than CEA⁺/Exo in inducing CEA-specific CTL response and suggest that exosomes derived from heat-stressed tumor cells may be used as efficient vaccine for cancer immunotherapy.

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