Trembath Dimitri G, Ivanova Anastasia, Krauze Michal T, Kirkwood John M, Nikolaishvilli-Feinberg Nana, Moschos Stergios J
Department of Pathology and Laboratory Medicine.
Department of Biostatistics.
Melanoma Res. 2021 Jun 1;31(3):264-267. doi: 10.1097/CMR.0000000000000731.
PTEN and p16 frequently undergo (epi)genetic aberrations in melanoma resulting in decreased, or absent, protein levels. We investigated the prognostic significance of these tumor suppressor genes in melanoma brain metastases (MBMs). Immunohistochemical analysis was performed on archived tissue sections from craniotomies. Expression of PTEN and p16 was semiquantitatively scored (0-3 scale) in melanoma cells, glia, TILs, and endothelial cells of tumor-associated vessels and was compared among the different brain tumor cell compartments. Overall survival (OS) analysis was performed according to PTEN and p16 protein expression in melanoma cells. 58 patients (median age 56, 37 male) underwent craniotomy for MBMs before February 2014. The OS of patients with decreased, or absent, protein expression (0, 1+) of PTEN and p16 in melanoma cells was significantly shorter compared to that of patients with high (2+, 3+) expression (median OS 2.40 vs. 10.75 months and 4.1 vs. 8.1 months, respectively; Gehan-Breslow-Wilcoxon test P = 0.026 and P = 0.037, respectively). PTEN and p16 protein expression were significantly lower in TILs compared to melanoma cells (Mann-Whitney test P = 0.023 and P < 0.0001, respectively). Low/absent protein expression of PTEN/p16 is an adverse prognostic factor in MBMs. Surprisingly, expression of both PTEN and p16 proteins was significantly lower in TILs compared to melanoma cells. Proliferating (p16 absent/low) TILs within the brain with or without an active PI3K-Akt pathway (PTEN absent/low) may represent a favorable host response in MBMs. Thus, treatment of patients with MBMs with CDK4/6 or PI3K pathway inhibitors may result in an unfavorable, bystander, off-target effect on host immune response.
在黑色素瘤中，PTEN和p16经常发生（表观）遗传畸变，导致蛋白水平降低或缺失。我们研究了这些肿瘤抑制基因在黑色素瘤脑转移（MBM）中的预后意义。对开颅手术存档组织切片进行免疫组织化学分析。在肿瘤相关血管的黑色素瘤细胞、神经胶质细胞、肿瘤浸润淋巴细胞（TIL）和内皮细胞中，对PTEN和p16的表达进行半定量评分（0 - 3分），并在不同脑肿瘤细胞区室之间进行比较。根据黑色素瘤细胞中PTEN和p16蛋白表达进行总生存期（OS）分析。2014年2月前，58例患者（中位年龄56岁，37例男性）因MBM接受开颅手术。黑色素瘤细胞中PTEN和p16蛋白表达降低或缺失（0、1 +）的患者的OS明显短于高表达（2 +、3 +）的患者（中位OS分别为2.40个月对10.75个月和4.1个月对8.1个月；Gehan - Breslow - Wilcoxon检验，P分别为0.026和0.037）。与黑色素瘤细胞相比，TIL中PTEN和p16蛋白表达显著降低（Mann - Whitney检验，P分别为0.023和P < 0.0001）。PTEN/p16蛋白低表达/缺失是MBM的不良预后因素。令人惊讶的是，与黑色素瘤细胞相比，TIL中PTEN和p16蛋白的表达均显著降低。大脑中增殖的（p16缺失/低表达）TIL，无论有无活跃的PI3K - Akt途径（PTEN缺失/低表达），可能代表MBM中一种有利的宿主反应。因此，用CDK4/6或PI3K途径抑制剂治疗MBM患者可能会对宿主免疫反应产生不利的旁观者脱靶效应。
