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.

中文翻译：

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肿瘤抑制蛋白 p16 和 PTEN 的黑色素瘤特异性表达是已确定的黑色素瘤脑转移的有利预后因素。

PTEN 和 p16 在黑色素瘤中经常发生（表观）遗传畸变，导致蛋白质水平降低或缺失。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。对开颅手术存档的组织切片进行免疫组织化学分析。对黑色素瘤细胞、神经胶质细胞、TIL 和肿瘤相关血管内皮细胞中 PTEN 和 p16 的表达进行半定量评分（0-3 级），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 蛋白的表达情况进行总生存 (OS) 分析。58 名患者（中位年龄 56 岁，其中 37 名男性）在 2014 年 2 月之前接受了开颅手术以进行 MBM。黑色素瘤细胞中 PTEN 和 p16 蛋白表达 (0, 1+) 降低或缺失的患者的 OS 明显短于高 (2+、3+) 表达的患者（中位 OS 分别为 2.40 与 10.75 个月和 4.1 与 8.1 个月；Gehan-Breslow-Wilcoxon 检验分别为 P = 0.026 和 P = 0.037）。与黑色素瘤细胞相比，TIL 中的 PTEN 和 p16 蛋白表达显着降低（Mann-Whitney 检验分别为 P = 0.023 和 P < 0.0001）。PTEN/p16 蛋白表达低/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 蛋白的表达显着降低。无论有或没有活跃的 PI3K-Akt 通路（PTEN 缺失/低），脑内 TIL 的增殖（p16 缺失/低）可能代表 MBM 中有利的宿主反应。因此，用 CDK4/6 或 PI3K 通路抑制剂治疗 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。