Melanoma-targeted chemo-thermo-immuno (CTI)-therapy using N-propionyl-4-S-cysteaminylphenol-magnetite nanoparticles elicits CTL response via heat shock protein-peptide complex release.
Melanogenesis substrate, N-propionyl-4-S-cysteaminylphenol (NPrCAP) is specifically taken up by melanoma cells and inhibits their growth by producing cytotxic free radicals. By taking advantage of this unique chemical agent, we have established melanoma-targeting intracellular hyperthermia by conjugating NPrCAP with magnetite nanoparticles (NPrCAP/M) upon exposure to an alternating magnetic field (AMF). This treatment causes cytotoxic reaction as well as heat shock responses, leading to elicitation of antitumor immune response, which was proved by tumor rechallenge test and CTL induction. We found the level of heat shock protein 72 (Hsp72) to be increased in the cell lysate and culture supernatant after intracellular hyperthermia. Melanoma-specific CD8(+) T-cell response to dendritic cells loaded with hyperthermia-treated tumor lysate was enhanced when compared with non-treated tumor lysate. When heat shock protein, particularly Hsp72, was immuno-depleted from hyperthermia-treated tumor cell lysate, specific CD8(+) T-cell response was abolished. Thus, it is suggested that antitumor immune response induced by hyperthermia using NPrCAP/M is derived from the release of HSP-peptide complex from degraded tumor cells. Therefore, this chemo-thermo-immuno (CTI)-therapy might be effective not only for primary melanoma but also for distant metastasis because of induction of systemic antimelanoma immune responses.
Sato
Akiko
A
Department of Dermatology, Faculty of Engineering, Kyusyu University, Fukuoka, Japan.
Tamura
Yasuaki
Y
Sato
Noriyuki
N
Yamashita
Toshiharu
T
Takada
Tomoaki
T
Sato
Makito
M
Osai
Yasue
Y
Okura
Masae
M
Ono
Ichiro
I
Ito
Akira
A
Honda
Hiroyuki
H
Wakamatsu
Kazumasa
K
Ito
Shosuke
S
Jimbow
Kowichi
K
D000818:Animals; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology; D003538:Cystamine / Q000031:analogs & derivatives* / Q000737:chemistry; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004574:Electromagnetic Fields; D005260:Female; D050884:HSP72 Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000276:immunology* / Q000378:metabolism; D006358:Hot Temperature; D006979:Hyperthermia, Induced; D058185:Magnetite Nanoparticles / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D010636:Phenols / Q000737:chemistry*; D011485:Protein Binding; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D058185:Magnetite Nanoparticles; C114098:N-propionyl-4-S-cysteaminylphenol; D010455:Peptides; D010636:Phenols; D003538:Cystamine