Intracellular Tumor-Associated Antigens Represent Effective Targets for Passive Immunotherapy
Intracellular Tumor-Associated Antigens Represent Effective Targets for Passive Immunotherapy
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DOI：
10.1158/0008-5472.can-11-3072
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Nishikawa, Hiroyoshi
中科院分区：
文献类型：
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作者：
Noguchi, Takuro;Kato, Takuma;Nishikawa, Hiroyoshi
针对肿瘤表面表达的肿瘤抗原的单克隆抗体 (mAb) 疗法与临床获益相关。然而，许多肿瘤抗原是细胞内分子，通常不被认为是 mAb 疗法的合适靶标。在这项研究中，我们通过研究针对 NY-ESO-1 的 mAb 的功效，提供了质疑这一观点的证据，NY-ESO-1 是人类肿瘤中广泛表达的免疫原，在细胞内表达，而不是在细胞表面表达。 NY-ESO-1 mAb 本身既不能增强抗原特异性 CD8(+) T 细胞诱导，也不能消除肿瘤。为了促进 mAb 接近细胞内靶分子，我们将抗 NY-ESO-1 mAb 与抗癌药物结合，以增强垂死肿瘤细胞释放细胞内 NY-ESO-1。引人注目的是，联合治疗诱导了强烈的抗肿瘤作用，并伴随着 NY-ESO-1 特异性效应/记忆 CD8(+) T 细胞的发展，而单独治疗无法引发这种作用。这种组合效应还与树突状细胞成熟标志物的上调有关，这与有效的抗肿瘤 T 细胞反应的组织一致。对 Fc γ 受体缺陷的宿主小鼠施用 Fc 耗尽的 F(ab) mAb 或联合治疗消除了治疗效果。总之，我们的研究结果表明，单克隆抗体可以捕获细胞内肿瘤抗原，并有效诱导 CD8(+) T 细胞反应，从而极大地扩展了单克隆抗体在被动癌症免疫治疗中的可能用途。癌症研究； 72（7）； 1672-82。 (C)2012 AACR。
Monoclonal antibody (mAb) therapy against tumor antigens expressed on the tumor surface is associated with clinical benefit. However, many tumor antigens are intracellular molecules that generally would not be considered suitable targets for mAbtherapy. In this study, we provide evidence challenging this view through an investigation of the efficacy of mAb directed against NY-ESO-1, a widely expressed immunogen in human tumors that is expressed intracellularly rather than on the surface of cells. On their own, NY-ESO-1 mAb could neither augment antigen-specific CD8(+) T-cell induction nor cause tumor eradication. To facilitate mAb access to intracellular target molecules, we combined anti-NY-ESO-1 mAb with anticancer drugs to accentuate the release of intracellular NY-ESO-1 from dying tumor cells. Strikingly, combination therapy induced a strong antitumor effect that was accompanied by the development of NY-ESO-1-specific effector/memory CD8(+) T cells that were not elicited by single treatments alone. The combinatorial effect was also associated with upregulation of maturation markers on dendritic cells, consistent with the organization of an effective antitumor T-cell response. Administration of Fc-depleted F(ab) mAb or combination treatment in Fc gamma receptor-deficient host mice abolished the therapeutic effect. Together, our findings show that intracellular tumor antigens can be captured by mAbs and engaged in an efficient induction of CD8(+) T-cell responses, greatly expanding the possible use of mAb for passive cancer immunotherapy. Cancer Res; 72(7); 1672-82. (C)2012 AACR.