免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
探索伴远处转移的原发性鼻窦黏膜黑色素瘤的分子特征及治疗策略
英文原题：Exploring Molecular Characteristics and Therapeutic Strategies for Primary Sinonasal Mucosal Melanoma With Distant Metastasis.
查看英文原题
Exploring Molecular Characteristics and Therapeutic Strategies for Primary Sinonasal Mucosal Melanoma With Distant Metastasis.
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中文摘要
鼻腔鼻窦黏膜黑色素瘤（SNMM）是一种罕见的鼻腔鼻窦道侵袭性恶性肿瘤。由于其临床表现较晚且常于晚期才被诊断，5年生存率<30%，而发生远处转移的患者（SNMM-M）预后更差。
因此，阐明SNMM的分子图谱可能为SNMM-M提供新的治疗靶点。本研究旨在通过靶向DNA和RNA下一代测序、免疫组织化学和荧光原位杂交，解析SNMM-M的组织病理学和分子图谱，并为潜在的治疗方法提供新的见解。SNMM-M病例的特征为上皮样形态为主、常见肿瘤坏死、多形性极少以及TIL（肿瘤浸润淋巴细胞）（TILs）稀疏。在SNMM中，缺乏活跃TILs与转移之间存在显著关联。
此外，淋巴血管侵犯的存在和缺乏活跃TILs均与SNMM患者较差的总体生存率显著相关。DNA和RNA测序均未发现基因融合，而DNA测序在186个基因中揭示了304个基因组改变，包括9个多打击基因。
值得注意的是，结构特异性核酸内切酶亚基（SLX4）——一种关键的同源重组修复支架蛋白——的错义突变仅在SNMM-M中检测到，且携带SLX4突变的患者生存期显著更差（中位生存期，9.9个月 vs 无SLX4突变的41.2个月；P < .0001）。对SNMM-M与无远处转移的SNMM（SNMM-nM）之间可临床干预基因的基因组改变和拷贝数变异进行的比较分析显示，CDK4获得/扩增常见于SNMM-M病例，而受体酪氨酸激酶和同源重组修复基因改变在SNMM-nM病例中高度富集。
此外，PD-L1在SNMM-nM中更常见表达。这些探索性发现提示，SLX4突变可能作为潜在的预后生物标志物，而CDK4抑制剂可能代表SNMM-M有前景的治疗选择。
然而，鉴于样本量有限，必须在更大规模的研究中进一步验证以确认这些发现。
展开英文摘要原文
Sinonasal mucosal melanoma (SNMM) is a rare aggressive malignancy of the sinonasal tract. Due to its advanced clinical presentation and frequent late-stage diagnosis, the 5-year survival rate is <30%, with an even worse prognosis in patients with distant metastasis (SNMM-M).
Therefore, characterizing the molecular landscape of SNMM may provide novel therapeutic targets for SNMM-M.
This study aimed to decipher the histopathological and molecular landscape of SNMM-M and yields novel insights into potential therapeutic approaches using targeted DNA and RNA next-generation sequencing, immunohistochemistry, and fluorescence in situ hybridization. SNMM-M cases were characterized by epithelioid-predominant morphology, frequent tumor necrosis, minimal pleomorphism, and sparse tumor-infiltrating lymphocytes (TILs). A significant association between the absence of brisk TILs and metastasis in SNMM was noted.
Moreover, the presence of lymphovascular invasion and absence of brisk TILs were both significantly associated with poorer overall survival in patients with SNMM. Both DNA and RNA sequencing identified no gene fusions, whereas DNA sequencing revealed 304 genomic alterations across 186 genes, including 9 multihit genes.
Notably, missense mutations in structure-specific endonuclease subunit (SLX4), a key homologous recombination repair scaffold protein, were exclusively detected in SNMM-M, and patients with SLX4 mutations exhibited significantly worse survival (median, 9. 9 vs 41. 2 months without SLX4 mutations; P < . 0001).
A comparative analysis of genomic alterations and copy number variations of clinically actionable genes between SNMM-M and SNMM without distant metastasis (SNMM-nM) revealed that CDK4 gains/amplifications were commonly seen in SNMM-M cases, whereas receptor tyrosine kinase and homologous recombination repair gene alterations were highly enriched in SNMM-nM cases.
Additionally, PD-L1 was more commonly expressed in SNMM-nM. These exploratory findings suggest that SLX4 mutation may serve as a potential prognostic biomarker and that CDK4 inhibitors could represent promising therapeutic options for SNMM-M.
However, given the limited sample size, further validation in larger studies is essential to confirm these findings.
论文信息
- 作者
- Ren D、Niu C、Htun N、Zhang X、He J、Li R、Liu Q、Lee V
- 单位
- Department of Pathology and Laboratory Medicine, University of California, Irvine, California. Electronic address: dren3@hs.uci.edu.United States
- 期刊
- Laboratory investigation; a journal of technical methods and pathology2025 Dec
- 原文标识
- PubMed 40914252 · DOI 10.1016/j.labinv.2025.104238
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