Karpathiou Georgia, Dridi Maroa, Krebs-Drouot Lila, Vassal François, Jouanneau Emmanuel, Jacquesson Timothée, Barrey Cédric, Prades Jean Michel, Dumollard Jean Marc, Meyronet David, Boutonnat Jean, Péoc'h Michel
Pathology Department, University Hospital of Saint-Etienne, 42055 Saint-Etienne, France.
Pathology Department, University Hospital of Grenoble, 38700 Grenoble, France.
Cancers (Basel). 2021 Apr 30;13(9):2169. doi: 10.3390/cancers13092169.
Chordomas are notably resistant to chemotherapy. One of the cytoprotective mechanisms implicated in chemoresistance is autophagy. There are indirect data that autophagy could be implicated in chordomas, but its presence has not been studied in chordoma tissues. Sixty-one (61) chordomas were immunohistochemically studied for autophagic markers and their expression was compared with the expression in notochords, clinicopathological data, as well as the tumor immune microenvironment. All chordomas strongly and diffusely expressed cytoplasmic p62 (sequestosome 1, SQSTM1/p62), whereas 16 (26.2%) tumors also showed nuclear p62 expression. LC3B (Microtubule-associated protein 1A/1B-light chain 3B) tumor cell expression was found in 44 (72.1%) tumors. Autophagy-related 16‑like 1 (ATG16L1) was also expressed by most tumors. All tumors expressed mannose-6-phosphate/insulin-like growth factor 2 receptor (M6PR/IGF2R). LC3B tumor cell expression was negatively associated with tumor size, while no other parameters, such as age, sex, localization, or survival, were associated with the immunohistochemical factors studied. LC3B immune cell expression showed a significant positive association with programmed death-ligand 1 (PD-L1)+ immune cells and with a higher vascular density. ATG16L1 expression was also positively associated with higher vascular density. Notochords ( = 5) showed different immunostaining with a very weak LC3B and M6PR expression, and no p62 expression. In contrast to normal notochords, autophagic factors such as LC3B and ATG16L1 are often present in chordomas, associated with a strong and diffuse expression of p62, suggesting a blocked autophagic flow. Furthermore, PD-L1+ immune cells also express LC3B, suggesting the need for further investigations between autophagy and the immune microenvironment.
脊索瘤对化疗具有显著抗性。自噬是与化疗抗性相关的细胞保护机制之一。有间接数据表明自噬可能与脊索瘤有关，但尚未在脊索瘤组织中研究其存在情况。对61例脊索瘤进行免疫组织化学研究，检测自噬标志物，并将其表达与脊索、临床病理数据以及肿瘤免疫微环境中的表达进行比较。所有脊索瘤均强烈且弥漫性表达细胞质p62（聚集体蛋白1，SQSTM1/p62），而16例（26.2%）肿瘤还显示出核p62表达。44例（72.1%）肿瘤中发现LC3B（微管相关蛋白1A/1B轻链3B）在肿瘤细胞中表达。大多数肿瘤也表达自噬相关16样蛋白1（ATG16L1）。所有肿瘤均表达甘露糖-6-磷酸/胰岛素样生长因子2受体（M6PR/IGF2R）。LC3B在肿瘤细胞中的表达与肿瘤大小呈负相关，而年龄、性别、定位或生存期等其他参数与所研究的免疫组织化学因素无关。LC3B在免疫细胞中的表达与程序性死亡配体1（PD-L1）+免疫细胞以及更高的血管密度呈显著正相关。ATG16L1的表达也与更高的血管密度呈正相关。脊索（n = 5）显示出不同的免疫染色，LC3B和M6PR表达非常弱，且无p62表达。与正常脊索不同，自噬因子如LC3B和ATG16L1在脊索瘤中经常存在，与p62的强烈且弥漫性表达相关，提示自噬流受阻。此外，PD-L1+免疫细胞也表达LC3B，表明需要进一步研究自噬与免疫微环境之间的关系。
