We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen induced murine model of OSCC. It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed the current study to further characterize the immune landscape of OPLs and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4NQO model. The immune pathways were targeted using monoclonal antibodies or, in the case of the PD-1/PD-L1 pathway, using PD-L1 knockout mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist monoclonal antibody was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1 knockout, also reduced progression of OPL to OSCC albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T-lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T-cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as a potential immunoprevention agents in this setting.

中文翻译：

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在致癌物诱导的口腔鳞状细胞癌模型中，靶向 CD40 和 PD-L1 通路抑制口腔癌前病变的进展

我们之前已经证明，PD-1 阻断降低了致癌物诱导的 OSCC 小鼠模型中高度不典型增生的发生率。然而，目前尚不清楚是否还有其他因素与逃避免疫监视有关，这些因素可以作为免疫预防的额外目标。我们进行了当前的研究，以进一步表征 OPL 的免疫景观，并确定 4NQO 模型中靶向 PD-1、CTLA-4、CD40 或 OX40 通路对 OPL 和口腔癌发展的影响。使用单克隆抗体靶向免疫途径，或者在 PD-1/PD-L1 途径的情况下，使用 PD-L1 敲除小鼠。干预后，采集舌头和颈部淋巴结并分别分析恶性进展和免疫环境的调节。用激动剂单克隆抗体靶向 CD40 是减少 OPL 向 OSCC 转变的最有效治疗方法；单独使用 PD-1 或​​与 CTLA-4 抑制或 PD-L1 敲除联合使用，也可减少 OPL 向 OSCC 的进展，尽管程度较轻。与有或没有 CTLA-4 阻断的 PD-1/PD-L1 轴阻断相比，CD40 激动剂观察到不同的免疫系统调节模式；CD40 激动剂产生了经验性/记忆性细胞毒性 T 淋巴细胞和 M1 巨噬细胞的持久扩增，而 PD-1/CTLA-4 阻断导致调节性 T 细胞的显着耗竭以及其他变化。这些数据表明，不同的方法可用于针对 OSCC 发展的不同步骤，并且 CD40 激动剂值得研究作为这种情况下的潜在免疫预防剂。