Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma
Antitumor Effects of Chimeric Receptor Engineered Human T Cells Directed to Tumor Stroma
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DOI：
10.1038/mt.2013.110
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发表时间：
2013-08-01
影响因子：
12.4
通讯作者：
Gottschalk, Stephen
中科院分区：
文献类型：
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作者：
Kakarla, Sunitha;Chow, Kevin K. H.;Gottschalk, Stephen
癌症相关成纤维细胞（CAFs）是肿瘤相关基质的主要成分，形成了一种高度促肿瘤发生和免疫抑制的微环境，介导治疗抗性。因此，除了癌细胞之外，共同靶向CAFs可能会增强抗肿瘤反应。成纤维细胞活化蛋白 -α（FAP），一种2型二肽基肽酶，在大多数实体瘤的CAFs上表达，使其成为一个有吸引力的免疫治疗靶点。为了靶向肿瘤相关基质中的FAP阳性CAFs，我们对T细胞进行基因改造，使其表达一种FAP特异性嵌合抗原受体（CAR）。由此产生的FAP特异性T细胞能够识别并杀死FAP阳性靶细胞，这通过促炎细胞因子释放和靶细胞裂解得以确定。在一个已建立的A549肺癌模型中，FAP特异性T细胞的过继转移显著减少了FAP阳性基质细胞，同时肿瘤生长也随之减少。将这些FAP特异性T细胞与靶向A549癌细胞自身上EphA2抗原的T细胞相结合，相较于单独使用任何一种，显著增强了整体抗肿瘤活性，并带来了生存优势。我们的研究强调了共同靶向CAFs和癌细胞以增加T细胞免疫疗法对实体瘤的益处的价值。
Cancer-associated fibroblasts (CAFs), the principle component of the tumor-associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-alpha (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP-specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co-targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors.