Wang Jin, Hu Yuan, Escamilla-Rivera Vicente, Gonzalez Cassandra L, Tang Lin, Wang Bingbing, El-Naggar Adel K, Myers Jeffrey N, Caulin Carlos
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of E.N.T., Shengjing Hospital of China Medical University, Shenyang 110004, China.
Cancers (Basel). 2021 Mar 23;13(6):1471. doi: 10.3390/cancers13061471.
Oral squamous cell carcinoma (OSCC) develops through the multistep malignant progression of squamous epithelium. This process can be prevented by PD-1 blockade in a mouse model for oral carcinogenesis. OSCCs exhibit a high incidence of mutations that confer oncogenic gain-of-function (GOF) activities that promote resistance to standard therapies and poor clinical outcomes. To determine whether epithelial mutations modulate anti-PD-1-mediated oral cancer immunoprevention, we generated mouse models for oral carcinogenesis by exposing mice carrying epithelial-specific mutations to the carcinogen 4NQO. Consistent with the oncogenic functions of mutant , mice with OSCCs expressing the GOF mutation developed higher metastasis rates than mice with loss-of-function (LOF) deletion or with wild-type . Throughout oral cancer progression, pre-invasive and invasive lesions showed a gradual increase in T-cell infiltration, recruitment of immunosuppressive regulatory T-cells (Tregs), and induction of PD-1/PD-L1 immune checkpoint proteins. Notably, while PD-1 blockade prevented the development of OSCCs in mice with wild-type or deletion, GOF abrogated the immunopreventive effects of anti-PD-1, associated with upregulation of IL17 signaling and depletion of exhausted CD8 cells in the microenvironment of the tumors. These findings sustain a potential role for profiling in personalized oral cancer immunoprevention.
口腔鳞状细胞癌（OSCC）通过鳞状上皮的多步骤恶性进展而发生。在口腔癌发生的小鼠模型中，PD-1阻断可预防这一过程。OSCCs表现出高发生率的突变，这些突变赋予致癌性功能获得（GOF）活性，从而促进对标准疗法的耐药性并导致不良临床结果。为了确定上皮突变是否调节抗PD-1介导的口腔癌免疫预防，我们通过将携带上皮特异性突变的小鼠暴露于致癌物4NQO来生成口腔癌发生的小鼠模型。与突变体的致癌功能一致，表达GOF突变的OSCC小鼠比具有功能丧失（LOF）缺失或野生型的小鼠发生更高的转移率。在整个口腔癌进展过程中，侵袭前和侵袭性病变显示T细胞浸润逐渐增加、免疫抑制调节性T细胞（Tregs）募集以及PD-1/PD-L1免疫检查点蛋白的诱导。值得注意的是，虽然PD-1阻断可预防野生型或缺失小鼠发生OSCC，但GOF突变消除了抗PD-1的免疫预防作用，这与IL17信号上调以及肿瘤微环境中耗竭的CD8细胞耗竭有关。这些发现支持了在个性化口腔癌免疫预防中进行突变谱分析的潜在作用。
