Institute of Photomedicine, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China.
J Transl Med. 2023 Nov 16;21(1):820. doi: 10.1186/s12967-023-04458-z.
UV-induced cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. The constant alterations of the lymphatic-centered immune microenvironment are essential in transforming from photoaging to cSCC. Studying the mechanism will be beneficial for new targets exploration to the early prediction of cSCC.
To investigate the dynamic changes and mechanism of the lymphatic-centered immune microenvironment in transforming from photoaging to cSCC induced by ultraviolet irradiation (UVR).
TIMER2.0 was used to analyze whether YAP1/VEGFC signaling pathway is involved in lymphangiogenesis in head and neck squamous cell carcinoma (HNSCC). Meanwhile, lymphatic-centered immune microenvironments alterations and the related cumulative survival time were also analyzed. With the accumulated UVR, skin photoaging developed and gradually progressed into actinic keratosis and cSCC on SKH-1 hairless mice. The skin lymphatic-centered immune microenvironment was evaluated at the 0th, 8th, 12th, 16-18th, and 20-24th week of UVR. Skin phenotype was assessed using optical coherence tomography (OCT) and skin image. H&E and Masson's trichrome staining evaluated epidermis and dermis. The structure of lymphatic vessels (LVs), blood vessels, and different types of T cells were evaluated by immunohistochemistry staining. The expression of Piezo1 whose deletion in adult lymphatics led to substantial valve degeneration, VE-cadherin that maintained the permeability of LVs, and YAP1 were evaluated by immunohistochemistry staining as well. Besides, the drainage function of LVs was assessed by Evans Blue assay in vivo.
The lymphatic function and immune cell infiltration underwent adaptive changes under continuous UVR. TIMER2.0 analysis indicated that VEGFC genes high expressed in HNSCC. YAP1 gene expression was positive correlated with VEGFC in HNSCC. LV density increased in human cSCC. More LVs in HNSCC were beneficial to prolong the survival time. VEGFC gene overexpression was positive correlated to CD8T cell infiltration. More CD8AT cells and CD8BT cell infiltration in HNSCC extended survival time. When YAP1 gene overexpression and high infiltration of endothelial cells took place simultaneously might prolong the survival time of HNSCC patients. And high infiltration of CD8T cells prolonged the survival time as well. In animal studies, UVR-induced eight weeks (photoaging) and 16-18 weeks (precancerous) were two turning points. The density of LVs in UV-8w was the least. When photoaged skin developed into AK lesions (UV-16-18w), LV slightly exceeded healthy skin and proliferated sharply in cSCC (UV-20-24w). YAP1 expression was almost consistent with LV but rose after the photoaging stage. The drainage of cSCC mice induced by UVR was better than that of photoaged skin and worse than that of health skin. The dynamic alterations of LVs number, Piezo1 expression, and collagen might be reasons for it. The expression of Piezo1 was in the highest point after 8 weeks of UVR, then gradually descended to the platform. The total T cells increased slowly, but the infiltration of CD4T cells increased, and CD8T cells decreased after eight weeks of UVR. The CD8T cells and CD4T cells increased sharply in UV-16-18w and UV-20-24w groups.
The lymphatic-centered immune microenvironment underwent adaptive changes under continuous UVR via regulating YAP1/VEGFC and Piezo1. During the formation of cSCC, there are two turning points, eight weeks (photoaging) and 16-18 weeks (precancerous). YAP1, Piezo1, LVs, and immune cells constantly changed with the skin state induced by UVR. According to these changes the process of cSCC can be identified in advance and intervene timely.
紫外线诱导的皮肤鳞状细胞癌（cSCC）是最常见的皮肤癌之一。淋巴中心免疫微环境的不断改变对于从光老化到 cSCC 的转化至关重要。研究其机制将有助于探索新的靶点，以实现 cSCC 的早期预测。
探讨紫外线照射（UVR）诱导的光老化向 cSCC 转化过程中以淋巴为中心的免疫微环境的动态变化及其机制。
使用 TIMER2.0 分析 YAP1/VEGFC 信号通路是否参与头颈部鳞状细胞癌（HNSCC）中的淋巴管生成。同时，还分析了以淋巴为中心的免疫微环境改变以及相关的累积生存时间。随着 UVR 的累积，皮肤光老化发展，并逐渐进展为光化性角化病和 cSCC，在 SKH-1 无毛小鼠上进行研究。在 UVR 的第 0、8、12、16-18 和 20-24 周评估皮肤以淋巴为中心的免疫微环境。使用光学相干断层扫描（OCT）和皮肤图像评估皮肤表型。H&E 和 Masson 三色染色评估表皮和真皮。通过免疫组织化学染色评估淋巴管（LV）、血管和不同类型 T 细胞的结构。通过免疫组织化学染色评估 Piezo1 的表达，Piezo1 在成年淋巴管中的缺失导致瓣膜严重退化，VE-cadherin 维持 LV 的通透性，以及 YAP1 的表达。此外，通过体内 Evans Blue 测定评估 LVs 的引流功能。
在连续 UVR 下，淋巴功能和免疫细胞浸润发生适应性变化。TIMER2.0 分析表明，VEGFC 基因在 HNSCC 中高表达。YAP1 基因表达与 HNSCC 中的 VEGFC 呈正相关。人 cSCC 中的 LV 密度增加。HNSCC 中更多的 LVs 有利于延长生存时间。VEGFC 基因过表达与 CD8T 细胞浸润呈正相关。HNSCC 中更多的 CD8A+T 细胞和 CD8B+T 细胞浸润延长了生存时间。当 YAP1 基因过表达和内皮细胞高浸润同时发生时，可能延长 HNSCC 患者的生存时间。而且高浸润的 CD8T 细胞也延长了生存时间。在动物研究中，UVR 诱导的 8 周（光老化）和 16-18 周（癌前病变）是两个转折点。UV-8w 中的 LV 密度最少。当光老化皮肤发展为 AK 病变（UV-16-18w）时，LV 略有超过健康皮肤，并在 cSCC（UV-20-24w）中急剧增殖。YAP1 表达几乎与 LV 一致，但在光老化阶段后上升。UVR 诱导的 cSCC 小鼠的引流情况优于光老化皮肤，劣于健康皮肤。LV 数量、Piezo1 表达和胶原蛋白的动态变化可能是原因。UVR 后 8 周 Piezo1 表达最高，然后逐渐下降至平台。总 T 细胞缓慢增加，但 CD4T 细胞浸润增加，CD8T 细胞减少。UV-16-18w 和 UV-20-24w 组中 CD8T 细胞和 CD4T 细胞急剧增加。
在连续 UVR 作用下，通过调节 YAP1/VEGFC 和 Piezo1，以淋巴为中心的免疫微环境发生适应性变化。在 cSCC 的形成过程中，有两个转折点，第 8 周（光老化）和 16-18 周（癌前病变）。YAP1、Piezo1、LVs 和免疫细胞随着 UVR 诱导的皮肤状态不断变化。根据这些变化，可以提前识别 cSCC 的进程并及时进行干预。
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