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PD-1 blockade prevents the progression of oral carcinogenesis.
Carcinogenesis ( IF 4.7 ) Pub Date : 2021-06-21 , DOI: 10.1093/carcin/bgab035
Yunmei Dong 1 , Zhen Wang 1 , Fei Mao 1 , Luyao Cai 1 , Hongxia Dan 1 , Lu Jiang 1 , Xin Zeng 1 , Taiwen Li 1 , Yu Zhou 1 , Qianming Chen 1
Affiliation  

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies in the head and neck with a poor prognosis. Oral cancer development is a multistep process involving carcinogenesis. Though significant advances in cancer immunotherapy over the years, there is lack of evidence for T-cell exhaustion during oral carcinogenesis. Clinical specimens from healthy donors and patients diagnosed with oral leukoplakia (OLK) or OSCC were collected for immunohistochemical staining with PD-L1, CD86, CD8, PD-1 and CTLA-4 antibodies. Meanwhile, chemically induced mouse models of oral carcinogenesis were constructed with 4-nitroquinolone-N-oxide induction. Exhaustion status of T cells was measured by flow cytometry for spleens and by multiplex immunohistochemistry for formalin-fixed paraffin-embedded lesions in multiple stages of oral carcinogenesis. The efficacy of PD-1 blockade with or without cisplatin treatment was evaluated on the mice in precancerous and OSCC stages. We observed higher expression of PD-1 in the human OLK and OSCC tissues compared with the normal, while low expression CTLA-4 in all oral mucosa tissues. Animal experiments showed that the exhausted CD4+ T cells existed much earlier than exhausted CD8+ T cells, and an increased ratio of stem-like exhausted T cells and partially exhausted T cells were detected in the experimental groups. Besides, the expression of immune checkpoint markers (PDCD1, CTLA4 and HAVCR2) was strongly positively correlated with cytokines (IFNG and IL-2). In summary, T-cell exhaustion plays a vital role in oral carcinogenesis, and PD-1 blockade can prevent the progression of oral carcinogenesis.

中文翻译:

PD-1 阻断可防止口腔癌发生的进展。

口腔鳞状细胞癌(OSCC)是头颈部最常见的恶性肿瘤之一,预后较差。口腔癌的发展是一个涉及致癌作用的多步骤过程。尽管多年来癌症免疫疗法取得了重大进展,但缺乏证据表明 T 细胞在口腔癌发生过程中会耗尽。收集来自健康供体和诊断为口腔白斑 (OLK) 或 OSCC 的患者的临床标本,用 PD-L1、CD86、CD8、PD-1 和 CTLA-4 抗体进行免疫组织化学染色。同时,用4-硝基喹诺酮-N-氧化物诱导构建了化学诱导的口腔癌发生小鼠模型。在口腔癌变的多个阶段,通过流式细胞术测量脾脏和通过多重免疫组织化学测量福尔马林固定石蜡包埋病变的 T 细胞衰竭状态。在癌症前期和 OSCC 阶段的小鼠中评估了 PD-1 阻断剂联合或不联合顺铂治疗的疗效。我们观察到与正常相比,人类 OLK 和 OSCC 组织中 PD-1 的表达更高,而所有口腔粘膜组织中 CTLA-4 的表达低。动物实验表明,衰竭的CD4+ T细胞比衰竭的CD8+ T细胞存在的时间要早​​得多,并且在实验组中检测到干细胞样衰竭T细胞和部分衰竭T细胞的比例增加。此外,免疫检查点标志物(PDCD1、CTLA4 和 HAVCR2)的表达与细胞因子(IFNG 和 IL-2)呈强正相关。综上所述,T细胞耗竭在口腔癌变中起着至关重要的作用,而PD-1阻断可以阻止口腔癌变的进展。
更新日期:2021-06-21
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