Magara Tetsuya, Nakamura Motoki, Nojiri Yuka, Yoshimitsu Maki, Kano Shinji, Kato Hiroshi, Morita Akimichi
Department of Geriatric and Environmental Dermatology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.
Front Oncol. 2023 Apr 4;13:1106434. doi: 10.3389/fonc.2023.1106434. eCollection 2023.
Cutaneous angiosarcoma (CAS) is a highly malignant tumor with few effective treatments. Although the indication for immune checkpoint inhibitors such as anti-PD-1 antibodies is expected to expand, there are many unknowns regarding the tumor immune microenvironment in CAS, which is generally considered an immunologically "cold" tumor. Our previous study demonstrated that tertiary lymphoid structures (TLSs) were associated with a favorable prognosis in CAS. However, we still don't know what the difference is between cases of TLS-rich and TLS-poor. Furthermore, the number of TLSs can vary significantly between lesions in the same case, for example, between primary and recurrence. To analyze the changes in the tumor immune microenvironment in CAS in more detail, we performed comprehensive RNA sequencing using a Next-generation sequencer (NGS). Sixty-two samples from 31 cases of CAS treated at Nagoya City University were collected. NGS and gene set enrichment analysis (GSEA) were performed on 15 samples among them. Immunohistochemistry and prognostic analysis by Kaplan-Meier method were performed on all 62 samples. NGS results showed that NY-ESO-1 (CTAG1B) was significantly upregulated in the TLS-positive cases. Immune checkpoint molecules including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) were upregulated in TLS-negative or TLS-low cases and seemed to associate with the suppression of TLS formation. In a comparison of primary and recurrent lesions, other cancer-testis antigens (CTAs) including XAGE-1B were significantly upregulated in recurrent lesions. The number of infiltrating CD8-positive cells and TLSs showed no significant trend between primary and recurrent lesions. However, the PD-L1 expression of tumor cells was significantly lower in recurrent than in primary lesions. Chemokines correlated with NY-ESO-1 expression were CCL21 and CXCL8, and only CCL21 correlated with the number of TLS. There was no chemokine associated with XAGE-1. NY-ESO-1 and XAGE-1 are detectable by immunohistochemistry. Although each cannot be a prognostic marker by itself, they can be a helpful marker in combination with the number of TLSs. CTAs play an essential role in forming the tumor immune microenvironment in CAS. These findings are evidence that CAS is an immunologically "hot" tumor and provides us with potential therapeutic targets and encourages the expansion of immunotherapy indications.
皮肤血管肉瘤（CAS）是一种恶性程度很高的肿瘤，有效治疗方法很少。尽管抗PD-1抗体等免疫检查点抑制剂的适应证有望扩大，但CAS的肿瘤免疫微环境仍有许多未知之处，CAS通常被认为是一种免疫“冷”肿瘤。我们之前的研究表明，三级淋巴结构（TLSs）与CAS的良好预后相关。然而，我们仍然不知道富含TLSs和缺乏TLSs的病例之间有何差异。此外，同一病例的不同病灶之间，例如原发灶和复发灶之间，TLSs的数量可能有显著差异。为了更详细地分析CAS中肿瘤免疫微环境的变化，我们使用下一代测序仪（NGS）进行了全面的RNA测序。收集了名古屋市立大学治疗的31例CAS患者的62个样本。对其中15个样本进行了NGS和基因集富集分析（GSEA）。对所有62个样本进行了免疫组织化学检测和Kaplan-Meier法预后分析。NGS结果显示，NY-ESO-1（CTAG1B）在TLS阳性病例中显著上调。程序性死亡-1（PD-1）和程序性死亡配体-1（PD-L1）等免疫检查点分子在TLS阴性或TLS低表达病例中上调，似乎与TLS形成的抑制有关。在原发灶和复发灶的比较中，包括XAGE-1B在内的其他癌胚抗原（CTAs）在复发灶中显著上调。浸润的CD8阳性细胞数量和TLSs数量在原发灶和复发灶之间没有显著趋势。然而，肿瘤细胞的PD-L1表达在复发灶中显著低于原发灶。与NY-ESO-1表达相关的趋化因子是CCL21和CXCL8，只有CCL21与TLSs数量相关。没有与XAGE-1相关的趋化因子。NY-ESO-1和XAGE-1可通过免疫组织化学检测到。虽然它们各自都不能单独作为预后标志物，但与TLSs数量联合使用时可能是有用的标志物。CTAs在CAS肿瘤免疫微环境的形成中起重要作用。这些发现证明CAS是一种免疫“热”肿瘤，为我们提供了潜在的治疗靶点，并鼓励扩大免疫治疗的适应证。
