Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Prev Res (Phila). 2021 Mar;14(3):313-324. doi: 10.1158/1940-6207.CAPR-20-0418. Epub 2020 Dec 4.
We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (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 this study to further characterize the immune landscape of oral premalignant lesions (OPL) 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 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1-knockout (PD-L1) 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 mAb 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, also reduced progression of OPLs 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 potential immunoprevention agents in this setting. PREVENTION RELEVANCE: PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted.
我们之前已经证明，在致癌物诱导的口腔鳞状细胞癌（OSCC）的小鼠模型中，PD-1 阻断可降低高级别发育不良的发生率。然而，尚不清楚是否有其他逃避免疫监视的因素可作为免疫预防的额外靶点。我们进行了这项研究，以进一步描述口腔癌前病变（OPL）的免疫景观，并确定靶向 PD-1、CTLA-4、CD40 或 OX40 途径对 4-硝基喹啉 1-氧化物模型中 OPL 和口腔癌发展的影响。使用 mAb 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（PD-L1）小鼠。干预后，分别采集舌头和颈部淋巴结进行恶性进展分析和免疫微环境调节分析。用激动性 mAb 靶向 CD40 是减少 OPL 向 OSCC 转化的最有效治疗方法；PD-1 单独或与 CTLA-4 抑制或 PD-L1 联合也可降低 OPL 向 OSCC 的进展，但程度较小。与 PD-1/PD-L1 轴阻断相比，CD40 激动剂具有不同的免疫系统调节模式；CD40 激动剂可持久扩增经验丰富/记忆细胞毒性 T 淋巴细胞和 M1 巨噬细胞，而 PD-1/CTLA-4 阻断则导致调节性 T 细胞显著耗竭以及其他变化。这些数据表明，不同的方法可用于靶向 OSCC 发展的不同阶段，CD40 激动剂作为该环境下的潜在免疫预防剂值得进一步研究。预防相关性：PD-1/PD-L1 途径阻断以及 CD40 途径的激活可在小鼠模型中防止 OPL 进展为侵袭性 OSCC。当靶向 CD40 或 PD-1/PD-L1 途径时，观察到不同的免疫调节模式。
