loss-of-function (TP53LOF) mutations might be a driver of poor prognosis and chemoresistance in both human papillomavirus (HPV)-independent (HPV–) and HPV-associated (HPV+) penile squamous cell carcinoma (PSCC). Here, we aim to describe transcriptomic differences in the PSCC microenvironment stratified by TP53LOF and HPV status. We used single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing to obtain a comprehensive atlas of the cellular architecture of PSCC. TP53LOF and HPV status were determined by targeted next-generation sequencing and sequencing HPV-DNA reads. Six HPV+ TP53 wild type (WT), six HPV– TP53WT, and four TP53LOF PSCC samples and six controls were included. Immunohistochemistry and hematoxylin-eosin confirmed the morphological context of the observed signatures. Prognostic differences between patient groups were validated in 541 PSCC patients using Kaplan-Meier survival estimates. Patients with aberrant p53 staining fare much worse than patients with either HPV– or HPV+ tumors and WT p53 expression. Using scRNA-seq, we revealed 65 cell subtypes within 83 682 cells. TP53LOF tumors exhibit a partial epithelial-to-mesenchymal transition, immune-excluded, angiogenic, and morphologically invasive environment, underlying their aggressive phenotype. HPV– TP53WT tumors show stemness and immune exhaustion. HPV+ TP53WT tumors mirror normal epithelial maturation with upregulation of antibody-drug-conjugate targets and activation of innate immunity. Inherent to the scRNA-seq analysis, low sample size is a limitation and validation of signatures in large PSCC cohorts is needed. This first scRNA-seq atlas offers unprecedented in-depth insights into PSCC biology underlying prognostic differences based on and HPV status. Our findings provide clues for testing novel biomarker-driven therapies in PSCC. Here, we analyzed tissues of penile cancer at the level of individual cells, which helps us understand why patients who harbor a deactivating mutation in the gene do much worse than patients lacking such a mutation. Such an analysis may help us tailor future therapies based on gene mutations and human papillomavirus status of these tumors.

中文翻译：

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阴茎癌单细胞图谱揭示 TP53 突变是攻击性表型的驱动因素，无论人乳头瘤病毒状态如何，并为个性化治疗提供线索


功能丧失 (TP53LOF) 突变可能是人乳头瘤病毒 (HPV) 独立型 (HPV-) 和 HPV 相关型 (HPV+) 阴茎鳞状细胞癌 (PSCC) 预后不良和化疗耐药的驱动因素。在这里，我们的目标是描述按 TP53LOF 和 HPV 状态分层的 PSCC 微环境中的转录组差异。我们使用单细胞 RNA 测序 (scRNA-seq) 和 T 细胞受体测序来获得 PSCC 细胞结构的综合图谱。 TP53LOF 和 HPV 状态通过靶向下一代测序和 HPV-DNA 测序测序确定。包括 6 个 HPV+ TP53 野生型 (WT)、6 个 HPV-TP53WT 和 4 个 TP53LOF PSCC 样本以及 6 个对照。免疫组织化学和苏木精-伊红证实了观察到的特征的形态学背景。使用 Kaplan-Meier 生存估计在 541 名 PSCC 患者中验证了患者组之间的预后差异。 p53 染色异常的患者比 HPV- 或 HPV+ 肿瘤和 WT p53 表达的患者情况要差得多。使用 scRNA-seq，我们揭示了 83 682 个细胞中的 65 种细胞亚型。 TP53LOF 肿瘤表现出部分上皮-间质转化、免疫排斥、血管生成和形态侵袭性环境，这是其侵袭性表型的基础。 HPV-TP53WT 肿瘤表现出干性和免疫衰竭。 HPV+ TP53WT 肿瘤反映了正常的上皮成熟情况，抗体药物缀合物靶标上调并激活先天免疫。 scRNA-seq 分析固有的局限性是样本量较小，因此需要在大型 PSCC 队列中验证特征。第一份 scRNA-seq 图谱为 PSCC 生物学提供了前所未有的深入见解，这些见解基于 HPV 状态而导致预后差异。 我们的研究结果为测试 PSCC 的新型生物标志物驱动疗法提供了线索。在这里，我们在单个细胞水平上分析了阴茎癌组织，这有助于我们理解为什么携带基因失活突变的患者比缺乏这种突变的患者表现更差。这样的分析可以帮助我们根据这些肿瘤的基因突变和人乳头瘤病毒状态来定制未来的治疗方法。