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首页> 外文期刊>Cancer Immunology, Immunotherapy >Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2180–188-specific CD8+ CTLs in a perforin/granzyme-mediated and IFN-γ-dependent manner: application of Trp2180–188 peptides
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Intratumoral electroporation of IL-12 cDNA eradicates established melanomas by Trp2180–188-specific CD8+ CTLs in a perforin/granzyme-mediated and IFN-γ-dependent manner: application of Trp2180–188 peptides

机译:IL-12 cDNA的瘤内电穿孔可通过穿孔素/粒酶介导且依赖于IFN-γ的方式,通过Trp2 180-188 特异性CD8 + CTL消除已建立的黑色素瘤:Trp2 180-188的应用

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摘要

Intratumoral electroporation (IT-EP) with IL-12 cDNA (IT-EP/IL12) can lead to the eradication of established B16 melanoma tumors in mice. Here, we explore the immunological mechanism of the antitumor effects generated by this therapy. The results show that IT-EP/IL12 applied only once resulted in eradication in 70% animals with large established B16 tumors. Tumor eradication required the participation of CD8+ T cells, but not CD4+ T cells and NK cells. IT-EP/IL12 induced antigen-specific CD8+ T cell responses against the immunodominant Trp2180–188 epitope and generated a systemic response, resulting in significant therapeutic effects against distal, untreated tumors. The therapeutic effect of IT-EP/IL12 was absent in perforin-deficient mice, indicating that tumor elimination occurred through conventional perforin/granzyme lysis by CTLs. Moreover, this therapy induced some degree of immunological memory that protected approximately one-third of the cured mice against a subsequent tumor challenge. Moreover, antitumor efficacy and long-term protection against B16 were significantly improved by concurrent Trp2 peptide immunization through more induction of Ag-specific CTL responses and more attraction of IFN-γ-expressing CD8+ T cells into tumor sites. The antitumor effect of IT-EP/IL12 required the participation of IFN-γ, which was shown to induce MHC class I expression on B16 cells and increase the lytic activity of the CD8+ CTL generated by IT-EP/IL12. The results from these animal studies may help in the development of IT-EP/IL12 for cancer patients.
机译:用IL-12 cDNA(IT-EP / IL12)进行瘤内电穿孔(IT-EP)可以根除小鼠中已建立的B16黑色素瘤肿瘤。在这里,我们探讨了这种疗法产生的抗肿瘤作用的免疫机制。结果表明,仅应用一次IT-EP / IL12就能根除70%患有大型B16肿瘤的动物。消灭肿瘤需要CD8 + T细胞的参与,但不需要CD4 + T细胞和NK细胞的参与。 IT-EP / IL12诱导针对免疫优势Trp2 180-188 表位的抗原特异性CD8 + T细胞应答,并产生全身应答,从而对未治疗的远端肿瘤产生了显着的治疗作用。在缺乏穿孔素的小鼠中没有IT-EP / IL12的治疗作用,这表明肿瘤清除是通过CTL通过常规穿孔素/颗粒酶裂解而发生的。而且,这种疗法诱导了一定程度的免疫记忆,保护了大约三分之一的治愈小鼠免于随后的肿瘤攻击。此外,通过同时诱导Trp2肽免疫,可通过更多地诱导Ag特异性CTL反应和将表达IFN-γ的CD8 + T细胞更多地吸引到肿瘤部位来显着改善抗肿瘤功效和对B16的长期保护。 IT-EP / IL12的抗肿瘤作用需要IFN-γ的参与,这被证明可诱导MHC I类在B16细胞上的表达,并增加IT-EP / IL12产生的CD8 + CTL的裂解活性。这些动物研究的结果可能有助于癌症患者开发IT-EP / IL12。

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