PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells
PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells
复制标题
DOI：
10.1158/0008-5472.can-03-3259
复制
发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Gajewski, TF
中科院分区：
文献类型：
--
作者：
Blank, C;Brown, I;Gajewski, TF
尽管通过疫苗接种或过继转移可增加循环中肿瘤抗原特异性CD8(+) T细胞，但肿瘤进展仍常常因对效应功能产生抗性而发生。为建立一种用于确定肿瘤对抗原特异性细胞毒性T淋巴细胞（CTLs）抗性机制的模型，将免疫原性较差的B16 - F10黑色素瘤进行转导，使其表达K - b结合肽SIYRYYGL作为一种绿色荧光蛋白融合蛋白，该蛋白应能被高亲和力的2C T细胞受体转基因T细胞识别。尽管B16.SIY细胞高水平表达抗原，并在干扰素 - γ（IFN - γ）作用下诱导表达K - b，但它们很难被致敏的2C/RAG2(-/-) T细胞识别。对候选抑制性配体的筛选显示，在干扰素 - γ处理的B16 - F10细胞以及另外8种小鼠肿瘤和7种人黑色素瘤细胞系上，程序性死亡受体配体1（PD - L1）/B7H - 1升高。与野生型2C细胞相比，致敏的2C/RAG2(-/-)/PD - 1(-/-) T细胞在针对肿瘤细胞时显示出细胞因子产生增加、增殖增强以及细胞溶解活性提高。在效应阶段存在抗PD - L1抗体时可重现这种效应，但在致敏培养阶段则不会。在体内过继转移2C/RAG2(-/-)/PD - 1(-/-) T细胞在野生型2C细胞或细胞毒性T淋巴细胞相关抗原4（CTLA - 4）缺陷的2C细胞无法排斥肿瘤的条件下可导致肿瘤排斥。我们的研究结果支持干扰PD - L1/PD - 1相互作用以增强肿瘤微环境中肿瘤抗原特异性CD8(+) T细胞的效应功能。
Although increased circulating tumor antigen-specific CD8(+) T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the K-b-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express K-b in response to IFN-gamma, they were poorly recognized by primed 2C/RAG2(-/-) T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-gamma-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2(-/-)/PD-1(-/-) T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2(-/-)/PD-1(-/-) T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8(+) T cells in the tumor microenvironment.