PD-1 blockage delays murine squamous cell carcinoma development
PD-1 blockage delays murine squamous cell carcinoma development
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DOI：
10.1093/carcin/bgt305
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发表时间：
2014-02-01
期刊：
影响因子：
4.7
通讯作者：
Campanelli, Ana Paula
中科院分区：
文献类型：
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作者：
Belai, Eduardo Bertoli;de Oliveira, Carine Ervolino;Campanelli, Ana Paula
程序性死亡配体 1 (PD-1) 与其两个配体 [程序性死亡配体 1 (PD-L1) 和 PD-L2] 的结合与肿瘤反应性 T 细胞的抑制有关；然而，这种 T 细胞功能障碍的潜在机制尚不清楚。我们假设 PD-1 和 PD-L1 信号在一定程度上导致鳞状细胞癌 (SCC) 通过调节肿瘤环境逃避免疫抗肿瘤调节。在本研究中，我们使用 SCC 的多阶段模型来研究 PD-1/PD-L1 激活在肿瘤发展过程中的作用。与非致瘤对照小鼠相比，肿瘤部位表达 PD-1 的 CD4 和 CD8 T 细胞百分比增加，而肿瘤部位的 F4/80 巨噬细胞中 PD-L1 的表达尤其增加。此外，PD-1的全身免疫中和导致乳头状瘤数量减少和发病率延迟，随后细胞角蛋白表达差异，表明PD-1PD-L1相互作用通过下调抗肿瘤反应促进鳞状细胞癌的进展。事实上，阻断 PD-1 增加了 CD8 和 CD4 T 细胞的百分比，以及肿瘤部位的干扰素水平。我们的结果表明 PD-1 T 细胞参与鳞状细胞癌的发展和炎症免疫反应的调节。
Engagement of programmed death-1 (PD-1) with its two ligands [programmed death ligand-1 (PD-L1) and PD-L2] has been associated with the suppression of tumor-reactive T cells; however, the underlying mechanism for this T-cell dysfunction is not clear. We hypothesized that PD-1 and PD-L1 signals are, in part, responsible for squamous cell carcinoma (SCC) escape from immune antitumor regulation by modulation of the tumor environment. In the present study, we used a multistage model of SCC to examine the role of PD-1/PD-L1 activation during tumor development. Tumor sites presented an increased percentage of CD4 and CD8 T cells expressing PD-1 when compared with non-tumorigenic control mice, whereas the expression of PD-L1 was particularly increased in F4/80 macrophages in tumor sites. Further, the systemic immune neutralization of PD-1 resulted in a decreased number and delayed incidence rate of papillomas followed by a differential expression of cytokeratins, suggesting that the PD-1PD-L1 interaction contributes to the progression of SCC by downregulation of antitumor responses. In fact, blocking PD-1 increased the percentage of CD8 and CD4 T cells, and the levels of interferon- in the tumor sites. Our results indicated involvement of PD-1 T cells in SCC development and in the modulation of the inflammatory immune response.