尽管局部晚期口腔鳞状细胞癌（OCSCC）对标准治疗方式有部分反应，但仍提出了重大的临床挑战。本研究调查了这些肿瘤中程序性死亡配体 1 (PD-L1) 表达的预后意义，重点关注其与治疗结果和免疫微环境的关系。我们评估了 132 名 OCSCC 患者的肿瘤浸润淋巴细胞 (TIL)，以评估他们对生存的影响。使用 CD3、CD68、CD11c、PD-L1 和 P40 的多重免疫组织化学染色来探讨早期 (n=22) 和局部晚期 (n=36) OCSCC 患者与临床结果的相关性。这些初步发现通过癌症基因组图谱 163 个局部晚期 OCSCC 肿瘤队列中的差异基因表达分析、基因集富集和免疫细胞解卷积得到了验证。此外，对较小队列 (n=10) 的单细胞 RNA 测序 (scRNA-seq) 进一步表征了这些肿瘤中的 PD-L1hi 或 PD-L1lo 癌细胞。PD-L1 表达升高与患有癌症的患者的不良预后相关。接受标准辅助治疗的局部晚期 OCSCC，无论基于 TIL 评估的“热”或“冷”分类。 PD-L1hi 肿瘤表现出活跃的免疫反应表型，肿瘤微环境中富含 M1 巨噬细胞、CD8 T 细胞和 T 调节细胞。值得注意的是，PD-L1 表达对结果的负面影响主要归因于癌细胞而不是免疫细胞的表达。此外，scRNA-seq 揭示免疫相互作用对于癌细胞中 PD-L1 的上调并不重要，相反，涉及复杂的调控网络。此外，与早期肿瘤相比，PD-L1lo 局部晚期肿瘤表现出更复杂的通路富集和多样化的 T 细胞群。我们的研究结果强调了局部晚期 OCSCC 中 PD-L1 表达的预后意义，并揭示了 PD-L1 表达与早期肿瘤之间复杂的相互作用。肿瘤微环境中的 PD-L1 表达、免疫反应和分子途径。这项研究提供的见解可能会为未来的治疗策略提供信息，包括为 PD-L1hi 局部晚期 OCSCC 患者量身定制免疫治疗方法的可能性。© 作者（或其雇主）2024。CC BY 允许重复使用-NC。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Locally advanced oral cavity squamous cell carcinoma (OCSCC) presents a significant clinical challenge despite being partially responsive to standard treatment modalities. This study investigates the prognostic implications of programmed death-ligand 1 (PD-L1) expression in these tumors, focusing on its association with treatment outcomes and the immune microenvironment.We assessed tumor-infiltrating lymphocytes (TILs) in 132 patients with OCSCC to evaluate their impact on survival. Multiplex immunohistochemistry staining for CD3, CD68, CD11c, PD-L1, and P40 was used to explore correlations with clinical outcomes in patients with early-stage (n=22) and locally advanced (n=36) OCSCC. These initial findings were validated through differential gene expression analysis, gene set enrichment, and immune cell deconvolution in a The Cancer Genome Atlas cohort of 163 locally advanced OCSCC tumors. Additionally, single-cell RNA sequencing (scRNA-seq) on a smaller cohort (n=10) further characterized the PD-L1hi or PD-L1lo cancer cells in these tumors.Elevated PD-L1 expression was associated with poor outcomes in patients with locally advanced OCSCC undergoing standard adjuvant therapy, irrespective of "hot" or "cold" classification based on TILs assessment. PD-L1hi tumors exhibited an active immune response phenotype, enriched with M1 macrophages, CD8+ T cells and T regulatory cells in the tumor microenvironment. Notably, the negative impact of PD-L1 expression on outcomes was primarily attributed to its expression by cancer cells, rather than immune cells. Furthermore, scRNA-seq revealed that immune interactions were not essential for PD-L1 upregulation in cancer cells, instead, complex regulatory networks were involved. Additionally, PD-L1lo locally advanced tumors exhibited more complex pathway enrichment and diverse T-cell populations compared with those in the early-stage.Our findings underscore the prognostic significance of PD-L1 expression in locally advanced OCSCC, and unveil the complex interplay between PD-L1 expression, immune responses, and molecular pathways in the tumor microenvironment. This study provides insights that may inform future therapeutic strategies, including the possibility of tailored immunotherapeutic approaches for patients with PD-L1hi locally advanced OCSCC.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.