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Abstract：
Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide, with human papillomavirus (HPV) infection contributing to cancer development. Conventional therapies achieve only limited efficiency, especially in recurrent or metastatic HNSCC. As the immune landscape decisively impacts the survival of patients and treatment efficacy, this study comprehensively investigated the immunological tumor microenvironment (TME) and its association with patient outcome, with special focus on several dendritic cell (DC) and T lymphocyte subpopulations. Therefore, formalin-fixed paraffin-embedded tumor samples of 56 HNSCC patients, who have undergone resection and adjuvant radiotherapy, were analyzed by multiplex immunohistochemistry focusing on the detailed phenotypic characterization and spatial distribution of DCs, CD8+ T cells, and T-helper cell subsets in different tumor compartments. Immune cell densities and proportions were correlated with clinical characteristics of the whole HNSCC cohort and different HPV- or hypoxia-associated subcohorts. Tumor stroma was highly infiltrated by plasmacytoid DCs and T lymphocytes. Among the T-helper cells and CD8+ T cells, stromal regulatory T cells and intraepithelial exhausted CD8+ T cells expressing programmed cell death protein-1 (PD-1+) and/or lymphocyte-activation gene-3 (LAG-3+) were the predominant phenotypes, indicating an immunosuppressive TME. HPV-associated tumors showed significantly higher infiltration of type I and type II conventional DCs (cDC1, cDC2) as well as several CD8+ T cell phenotypes including exhausted, activated, and proliferating T cells. On the contrary, tumors with hypoxia-associated gene signatures exhibited reduced infiltration for these immune cells. By multivariate Cox regression, immune-related prognostic factors were identified. Patient clusters defined by high infiltration of DCs and T lymphocytes combined with HPV positivity or low hypoxia showed significantly prolonged survival. Thereby, cDC1 and CD8+ T cells emerged as independent prognostic factors for local and distant recurrence. These results might contribute to the implementation of an immune cell infiltration score predicting HNSCC patients\' survival and such patient stratification might improve the design of future individualized radiochemo-(immuno)therapies.
摘要：
头颈部鳞状细胞癌（HNSCC）是全球最常见的肿瘤之一，人乳头瘤病毒（HPV）感染有助于癌症的发展。传统疗法只能达到有限的效率，尤其是复发或转移性HNSCC。由于免疫景观决定性地影响患者的生存和治疗效果，这项研究全面调查了免疫肿瘤微环境（TME）及其与患者预后的关系，特别关注几种树突状细胞（DC）和T淋巴细胞亚群。因此,56例HNSCC患者的福尔马林固定石蜡包埋肿瘤样本，接受过切除和辅助放疗的人，通过多重免疫组织化学分析DCs的详细表型特征和空间分布，CD8+T细胞，和不同肿瘤区室的T辅助细胞亚群。免疫细胞密度和比例与整个HNSCC队列和不同的HPV或缺氧相关亚组的临床特征相关。浆细胞样DC和T淋巴细胞高度浸润肿瘤基质。在T辅助细胞和CD8+T细胞中，表达程序性细胞死亡蛋白-1(PD-1+)和/或淋巴细胞活化基因-3(LAG-3+)的基质调节性T细胞和上皮内耗尽的CD8+T细胞是主要的表型,表明免疫抑制性TME。HPV相关肿瘤显示I型和II型常规DC（cDC1，cDC2）以及几种CD8T细胞表型（包括耗尽，激活,和增殖T细胞。相反,具有缺氧相关基因特征的肿瘤对这些免疫细胞的浸润减少.通过多元Cox回归，确定了免疫相关的预后因素.由DC和T淋巴细胞的高浸润结合HPV阳性或低缺氧定义的患者簇显示出显著延长的存活。因此，cDC1和CD8+T细胞是局部和远处复发的独立预后因素。这些结果可能有助于实施预测HNSCC患者生存的免疫细胞浸润评分，这种患者分层可能会改善未来个性化放化疗（免疫）治疗的设计。
