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

Clin Cancer Res. 2005 Oct 15;11(20):7554-63. doi: 10.1158/1078-0432.CCR-05-0810.

Abstract

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/Kb 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/Kb 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / isolation & purification
  • Carcinoembryonic Antigen / immunology*
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy
  • Cytotoxicity Tests, Immunologic
  • Cytotoxicity, Immunologic / immunology
  • HLA-A Antigens / genetics
  • HLA-A Antigens / immunology*
  • HLA-A2 Antigen
  • HSP70 Heat-Shock Proteins / immunology
  • Hot Temperature
  • Humans
  • Immunization
  • Immunotherapy, Adoptive
  • Lymphocyte Culture Test, Mixed
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Xenograft Model Antitumor Assays

Substances

  • Cancer Vaccines
  • Carcinoembryonic Antigen
  • HLA-A Antigens
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • HSP70 Heat-Shock Proteins