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

Purpose: Tumor-derived exosomes are proposed as a new type of cancer vaccine. Heat shock proteins are potentTh1 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.