Although the principle of systemic treatment to prevent the progression of oral premalignant lesions (OPL) has been demonstrated, there remains a lack of consensus about an optimal approach that balances clinical efficacy with toxicity concerns. Recent advances in cancer therapy using approaches targeting the tumor immune microenvironment (TIME) including immune-checkpoint inhibitors indicate that these agents have significant clinically activity against different types of cancers, including oral cancer, and therefore they may provide an effective oral cancer prevention strategy for patients with OPLs. Our past work showed that systemic delivery of a monoclonal antibody to the programmed death receptor 1 (PD-1) immune checkpoint can inhibit the progression of OPLs to oral cancer in a syngeneic murine oral carcinogenesis model. Here we report a novel approach of local delivery of a PD-1 immune-checkpoint inhibitor loaded using a hydrogel, which significantly reduces the progression of OPLs to carcinomas. In addition, we detected a significant infiltration of regulatory T cells associated with oral lesions with p53 mutation, and a severe loss of expression of STING, which correlated with a decreased infiltration of dendritic cells in the oral lesions. However, a single local dose of PD-1 inhibitor was found to restore stimulator of interferon response cGAMP interactor 1 (STING) and CD11c expression and increase the infiltration of CD8+ T cells into the TIME irrespective of the p53 mutational status. Overall, we provide evidence for the potential clinical value of local delivery of biomaterials loaded with anti–PD-1 antibodies to prevent malignant progression of OPLs. Prevention Relevance: Oral cancer is an aggressive disease, with an overall survival rate of 50%. Preinvasive histologic abnormalities such as tongue dysplasia represent an early stage of oral cancer; however, there are no treatments to prevent oral carcinoma progression. Here, we combined biomaterials loaded with an immunotherapeutic agent preventing oral cancer progression.

中文翻译：

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局部抗 PD-1 递送可防止 4NQO-口腔致癌小鼠模型中癌前病变的进展

尽管已经证明了预防口腔癌前病变 (OPL) 进展的全身治疗原则，但对于平衡临床疗效和毒性问题的最佳方法仍缺乏共识。使用针对肿瘤免疫微环境 (TIME) 的方法（包括免疫检查点抑制剂）进行癌症治疗的最新进展表明，这些药物对不同类型的癌症（包括口腔癌）具有显着的临床活性，因此它们可能为口腔癌的预防提供有效的策略。患有 OPL 的患者。我们过去的工作表明，在同基因小鼠口腔癌发生模型中，对程序性死亡受体 1 (PD-1) 免疫检查点的单克隆抗体的全身递送可以抑制 OPL 向口腔癌的进展。在这里，我们报告了一种使用水凝胶局部递送 PD-1 免疫检查点抑制剂的新方法，该方法显着降低了 OPL 向癌症的进展。此外，我们检测到与具有 p53 突变的口腔病变相关的调节性 T 细胞的显着浸润，以及 STING 表达的严重丧失，这与口腔病变中树突状细胞的浸润减少相关。然而，发现单次局部剂量的 PD-1 抑制剂可恢复干扰素反应刺激物 cGAMP 相互作用物 1 (STING) 和 CD11c 的表达，并增加 CD8+ T 细胞在 TIME 中的浸润，而与 p53 突变状态无关。总体而言，我们为局部递送负载抗 PD-1 抗体的生物材料预防 OPL 恶性进展的潜在临床价值提供了证据。预防相关性：口腔癌是一种侵袭性疾病，总生存率为 50%。舌发育不良等侵袭前组织学异常代表口腔癌的早期阶段。然而，没有预防口腔癌进展的治疗方法。在这里，我们将装载有免疫治疗剂的生物材料结合起来，防止口腔癌进展。