Department of Immunotechnology, Lund University, Lund, Sweden.
Department of ORL, Head & Neck Surgery, Skåne University Hospital, Lund, Sweden.
Front Immunol. 2023 Jan 19;13:1087843. doi: 10.3389/fimmu.2022.1087843. eCollection 2022.
The incidence of human papillomavirus-positive (HPV) tonsillar cancer has been sharply rising during the last decades. Myeloid cells represent an appropriate therapeutic target due to their proximity to virus-infected tumor cells, and their ability to orchestrate antigen-specific immunity, within the tonsil. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV tonsillar cancer. We observed an expansion of the myeloid compartment in HPV tonsillar cancer, accompanied by interferon-induced cellular responses both in dendritic cells (DCs) and monocyte-macrophages. Our analysis unveiled the existence of four DC lineages, two macrophage polarization processes, and their sequential maturation profiles. Within the DC lineages, we described a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC transcriptional program involving upregulation of interferon-inducible genes. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which give rise to either interferon-activated or CXCL-producing macrophages, the latter enriched in advanced tumor stages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1 and interferon-activated DCs and macrophages on patient survival using gene signature scoring. The current study contributes to the understanding of myeloid ontogeny and dynamics in HPV-driven tonsillar cancer, and highlights myeloid biomarkers that can be used to assess patient prognosis.
在过去几十年中，人乳头瘤病毒阳性（HPV）扁桃体癌的发病率急剧上升。由于髓样细胞靠近受病毒感染的肿瘤细胞，并且能够在扁桃体中协调抗原特异性免疫，因此它们是一种合适的治疗靶标。然而，稳态和炎症性髓样细胞亚群之间的相互关系及其对患者生存的影响仍未得到探索。在这里，我们使用单细胞 RNA 测序来绘制 HPV 扁桃体癌中的髓样细胞区室。我们观察到 HPV 扁桃体癌中髓样细胞区室的扩张，同时在树突状细胞（DC）和单核细胞-巨噬细胞中观察到干扰素诱导的细胞反应。我们的分析揭示了存在四种 DC 谱系，两种巨噬细胞极化过程及其顺序成熟谱。在 DC 谱系中，我们描述了祖细胞和成熟 cDC 之间频率的平衡转移，有利于 cDC1 谱系而不利于 cDC2。此外，我们观察到除了 DC5 之外的所有 DC 谱系都成熟为一种共同的激活 DC 转录程序，涉及干扰素诱导基因的上调。反过来，单核细胞-巨噬细胞谱系经历了早期单核细胞极化事件，导致干扰素激活或 CXCL 产生的巨噬细胞，后者在晚期肿瘤阶段富集。我们使用 26 plex 流式细胞术验证了大多数单细胞 RNA-seq 聚类的存在，并使用基因特征评分描述了 cDC1 和干扰素激活的 DC 和巨噬细胞对患者生存的积极影响。本研究有助于理解 HPV 驱动的扁桃体癌中髓样细胞的发生和动态，并突出了可用于评估患者预后的髓样生物标志物。
