Detection of Intra-Tumor Self Antigen Recognition during Melanoma Tumor Progression in Mice Using Advanced Multimode Confocal/Two Photon Microscope
Detection of Intra-Tumor Self Antigen Recognition during Melanoma Tumor Progression in Mice Using Advanced Multimode Confocal/Two Photon Microscope
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DOI：
10.1371/journal.pone.0021214
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发表时间：
2011-06-22
期刊：
影响因子：
3.7
通讯作者：
Wolchok, Jedd D.
中科院分区：
文献类型：
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作者：
Schaer, David A.;Li, Yongbiao;Wolchok, Jedd D.
确定肿瘤免疫是如何调节的需要了解在没有治疗干预的情况下抗肿瘤免疫应答在体内“起作用”的程度。为了更好地理解这个问题，我们开发了先进的多模式反射共聚焦/双光子荧光活体成像技术，与肿瘤特异性T细胞的传统离体分析结合使用。通过转移少量黑色素瘤特异性CD 8 + T细胞（Pmel-1），试图模拟生理条件，我们发现单独的B16肿瘤生长就足以诱导幼稚Pmel-1 T细胞增殖和获得效应表型。肿瘤致敏的Pmel-1 T细胞能够杀死外周中的靶细胞并分泌IFN γ，但不能介导肿瘤消退。在肿瘤内，Pmel-1 T细胞具有高度受限的移动性，显示出与肿瘤细胞的长期相互作用。相比之下，过继转移的非肿瘤特异性OT-I T细胞既不显示受限的移动性，也不显示与B16肿瘤细胞的长期相互作用，表明Pmel-1 T细胞对同源自身抗原的肿瘤内识别发生在肿瘤生长期间。总之，这些数据表明，抗肿瘤疗效的缺乏不仅仅是由于忽视肿瘤微环境中的自身抗原，而是由于主动免疫抑制影响阻止了保护性免疫应答。
Determining how tumor immunity is regulated requires understanding the extent to which the anti-tumor immune response "functions" in vivo without therapeutic intervention. To better understand this question, we developed advanced multimodal reflectance confocal/two photon fluorescence intra-vital imaging techniques to use in combination with traditional ex vivo analysis of tumor specific T cells. By transferring small numbers of melanoma-specific CD8+ T cells (Pmel-1), in an attempt to mimic physiologic conditions, we found that B16 tumor growth alone was sufficient to induce naive Pmel-1 T cell proliferation and acquisition of effector phenotype. Tumor-primed Pmel-1 T cells, are capable of killing target cells in the periphery and secrete IFN gamma, but are unable to mediate tumor regression. Within the tumor, Pmel-1 T cells have highly confined mobility, displaying long term interactions with tumor cells. In contrast, adoptively transferred non tumor-specific OT-I T cells show neither confined mobility, nor long term interaction with B16 tumor cells, suggesting that intra-tumor recognition of cognate self antigen by Pmel-1 T cells occurs during tumor growth. Together, these data indicate that lack of anti-tumor efficacy is not solely due to ignorance of self antigen in the tumor microenvironment but rather to active immunosuppressive influences preventing a protective immune response.