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
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
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DOI：
10.1111/j.1349-7006.2010.01623.x
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发表时间：
2010-09-01
期刊：
影响因子：
5.7
通讯作者：
Jimbow, Kowichi
中科院分区：
文献类型：
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作者：
Sato, Akiko;Tamura, Yasuaki;Jimbow, Kowichi
黑素生成底物N-丙酰-4-S-半胱氨基苯酚(NPrCAP)被黑色素瘤细胞特异性摄取，通过产生胞毒自由基抑制黑色素瘤细胞的生长。通过利用这种独特的化学试剂，我们通过在交变磁场(AMF)中将NPrCAP与磁性纳米颗粒(NPrCAP/M)偶联，建立了针对黑色素瘤的细胞内热疗。经肿瘤再激发试验和CTL诱导试验证实，该疗法可引起细胞毒反应和热休克反应，从而诱导抗肿瘤免疫反应。我们发现细胞内加温后，细胞裂解液和培养上清液中热休克蛋白72(HSP72)的水平升高。与未治疗的肿瘤裂解物相比，黑色素瘤特异性CD8+T细胞对负载了经高温处理的肿瘤裂解物的树突状细胞的反应增强。当热休克蛋白，特别是HSP72，从高温处理的肿瘤细胞裂解液中被去除免疫时，特异性CD8+T细胞反应被取消。因此，NPrCAP/M热疗诱导的抗肿瘤免疫反应可能来源于降解的肿瘤细胞释放热休克蛋白-多肽复合体。因此，这种化疗-热-免疫(CTI)疗法可能不仅对原发黑色素瘤有效，而且对远处转移也有效，因为它诱导了全身抗黑色素瘤免疫反应。(癌症科学2010)。
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. (Cancer Sci 2010).