Department of Pathology, School of Medicine, Johns Hopkins University, Bldg, CRBII Rm, 309, 1550 Orleans Street, Baltimore, Maryland 21231, USA.
Cell Biosci. 2013 Dec 20;3(1):48. doi: 10.1186/2045-3701-3-48.
There is an urgent need to develop targeted therapies for the control of advanced stage ovarian cancer because it is the most deadly gynecologic cancer. Antigen-specific immunotherapy is a promising approach because of the potential of the immune system to specifically target tumors without the toxicity associated with traditional chemoradiation. However, one of the major limitations for antigen-specific cancer immunotherapy is the pre-existing immune tolerance against endogenous targeted tumor antigens that frequently evolves during carcinogenesis. Here, we described the creation of a therapeutic agent comprised of a tumor-homing module fused to a functional domain capable of selectively rendering tumor cells sensitive to foreign antigen-specific CD8+ T cell-mediated immune attack, thereby circumventing many aspects of immune tolerance. The tumor-homing module, NKG2D, specifically binds to NKG2D ligand that is commonly overexpressed in ovarian tumors. The functional domain is comprised of the Fc portion of IgG2a protein and foreign immunogenic CD8+ T cell epitope flanked by furin cleavage sites (R), which can be recognized and cleaved by furin that is highly expressed in the tumor microenvironment.
We show that this therapeutic chimeric protein specifically loaded antigenic epitope onto the surface of NKG2D ligand-expressing ovarian tumor cells, rendering ovarian tumors susceptible to antigen-specific CTL-mediated killing in vitro. Furthermore, we show that intraperitoneal administration of our therapeutic chimeric protein followed by adoptive transfer of antigen-specific CD8+ T cells generates potent antitumor effects and significant accumulation of antigen-specific CD8+ T cells in the tumor loci.
Our findings have promise for bypassing immune tolerance to enhance cancer immunotherapy.
迫切需要开发针对晚期卵巢癌的靶向治疗方法，因为它是最致命的妇科癌症。抗原特异性免疫疗法是一种很有前途的方法，因为免疫系统有可能特异性地靶向肿瘤，而不会产生传统放化疗的毒性。然而，抗原特异性癌症免疫疗法的一个主要限制是针对内源性靶向肿瘤抗原的预先存在的免疫耐受，这种耐受通常在癌变过程中进化。在这里，我们描述了一种治疗剂的创建，该治疗剂由与能够选择性地使肿瘤细胞对外国抗原特异性 CD8+T 细胞介导的免疫攻击敏感的功能域融合的肿瘤归巢模块组成，从而规避了许多免疫耐受方面的问题。肿瘤归巢模块 NKG2D 特异性结合在卵巢肿瘤中普遍过表达的 NKG2D 配体。功能域由 IgG2a 蛋白的 Fc 部分和由 furin 切割位点 (R) 侧翼的外国免疫原性 CD8+T 细胞表位组成，该表位可被在肿瘤微环境中高度表达的 furin 识别和切割。
我们表明，这种治疗性嵌合蛋白特异性地将抗原表位加载到表达 NKG2D 配体的卵巢肿瘤细胞表面，使卵巢肿瘤易受抗原特异性 CTL 介导的杀伤作用。此外，我们表明，腹腔内给予我们的治疗性嵌合蛋白，然后过继转移抗原特异性 CD8+T 细胞，可在体内产生强大的抗肿瘤作用，并显著增加肿瘤部位的抗原特异性 CD8+T 细胞的积累。
我们的发现有希望克服免疫耐受，增强癌症免疫疗法。
