Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of E.N.T., Shengjing Hospital of China Medical University, Shenyang, China.
Cancer Prev Res (Phila). 2017 Dec;10(12):684-693. doi: 10.1158/1940-6207.CAPR-17-0108. Epub 2017 Oct 10.
Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPL). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti-PD-1 treatment significantly reduced the number of oral lesions that developed in these mice and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8 and CD4 T cells and the accumulation of CTLA-4 T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of IFNγ, STAT1 activation and the production of the T-cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T-cell activation mediates the immunopreventive effects of anti-PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti-PD-1. .
口腔鳞状细胞癌（OSCC）是由进行性口腔癌前病变（OPL）引起的。因此，预计预防 OPL 恶性进展的治疗策略将降低 OSCC 发展的发生率。靶向 T 细胞上的程序性死亡受体 1（PD-1）与癌细胞上的 PD-1 配体 PD-L1 相互作用的免疫检查点抑制剂已被证明可延长晚期 OSCC 患者的生存期。在这里，我们使用 4-硝基喹啉 1-氧化物（4-NQO）口腔致癌小鼠模型来检验 PD-1 阻断可能控制 OPL 进展的假设。小鼠在饮用水中暴露于 4-NQO，然后随机分配到两个治疗组，分别接受 PD-1 的阻断抗体或对照 IgG。我们发现抗 PD-1 治疗显著减少了这些小鼠中发展的口腔病变数量，并阻止了恶性进展。低级别异型增生病变对 PD-1 阻断有反应，CD8 和 CD4 T 细胞的募集以及 CTLA-4 T 细胞在其微环境中的积累显著增加。值得注意的是，PD-1 抑制伴随着 IFNγ的诱导、STAT1 激活和浸润细胞中 T 细胞效应分子颗粒酶 B 的产生，以及口腔病变上皮细胞的凋亡诱导，表明 T 细胞激活介导了抗 PD-1 的免疫预防作用。这些结果支持 PD-1 免疫检查点阻断预防 OSCC 发展和进展的潜在临床益处，并表明 CTLA-4 抑制剂可能增强抗 PD-1 的预防作用。
