Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.
Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting.
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DOI：
10.1038/nature10755
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发表时间：
2012-02-08
期刊：
影响因子：
64.8
通讯作者：
Schreiber, Robert D.
中科院分区：
文献类型：
--
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
癌症免疫编辑是免疫系统控制肿瘤生长和形成肿瘤免疫原性的过程，由三个阶段组成：消除，平衡和逃逸。虽然参与这一过程的许多免疫成分是已知的，但其潜在机制仍然不清楚。癌症免疫编辑的一个核心原则是T细胞对肿瘤抗原的识别驱动了正在发展的癌症的免疫破坏或雕刻。然而，我们目前对肿瘤抗原的理解主要来自对免疫活性宿主中发生的癌症的分析，因此可能已经被编辑过。关于新生肿瘤细胞中表达的抗原知之甚少，无论它们是否足以诱导保护性抗肿瘤免疫应答，或者它们的表达是否受到免疫系统的调节。在这里，使用大规模平行测序，我们表征了来自免疫缺陷Rag 2 −/−小鼠的高度免疫原性甲基胆蒽诱导的肉瘤中表达的突变，这些肉瘤表型类似于新生的原发性肿瘤细胞。采用I类预测算法，我们确定突变血影蛋白-β2作为d42 m1肉瘤的潜在排斥抗原，并通过常规抗原表达克隆和检测验证这一预测。我们还证明，d42 m1的癌症免疫编辑通过T细胞依赖性免疫选择过程发生，该过程促进缺乏高抗原性突变血影蛋白-β2和其他潜在强抗原的预先存在的肿瘤细胞克隆的生长。这些结果表明，未经编辑的肿瘤的强免疫原性可归因于高抗原性突变蛋白的表达，并表明缺乏这些强抗原的肿瘤细胞通过T细胞依赖性免疫选择过程的生长代表了癌症免疫编辑的一种机制。
Cancer immunoediting, the process whereby the immune system controls tumour outgrowth and shapes tumour immunogenicity, is comprised of three phases: elimination, equilibrium and escape. Although many immune components that participate in this process are known, its underlying mechanisms remain poorly defined. A central tenet of cancer immunoediting is that T cell recognition of tumour antigens drives the immunologic destruction or sculpting of a developing cancer. However, our current understanding of tumour antigens comes largely from analyses of cancers that develop in immunocompetent hosts and thus may have already been edited. Little is known about the antigens expressed in nascent tumour cells, whether they are sufficient to induce protective anti-tumour immune responses or whether their expression is modulated by the immune system. Here, using massively parallel sequencing, we characterize expressed mutations in highly immunogenic methylcholanthrene-induced sarcomas derived from immunodeficient Rag2−/− mice which phenotypically resemble nascent primary tumour cells. Employing class I prediction algorithms, we identify mutant spectrin-β2 as a potential rejection antigen of the d42m1 sarcoma and validate this prediction by conventional antigen expression cloning and detection. We also demonstrate that cancer immunoediting of d42m1 occurs via a T cell-dependent immunoselection process that promotes outgrowth of pre-existing tumour cell clones lacking highly antigenic mutant spectrin-β2 and other potential strong antigens. These results demonstrate that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and show that outgrowth of tumour cells that lack these strong antigens via a T cell-dependent immunoselection process represents one mechanism of cancer immunoediting.
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影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
MULLER, U;STEINHOFF, U;AGUET, M
通讯作者：
AGUET, M
影响因子：
32.4
作者：
DIGHE, AS;RICHARDS, E;SCHREIBER, RD
通讯作者：
SCHREIBER, RD