Background Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

中文翻译：

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恶性胸膜间皮瘤免疫微环境和检查点表达：随着时间的推移与临床病理特征和肿瘤内异质性相关。

背景肿瘤免疫微环境（TME）在恶性胸膜间皮瘤（MPM）发病机理和治疗结果中起关键作用，支持免疫检查点抑制剂作为抗癌手段的作用。这项研究回顾性研究了单纯MPM患者中TME和程序性死亡配体1（PD-L1）的表达及其在化疗后的变化。患者和方法MPM患者的诊断活检来自四个意大利和一个斯洛文尼亚癌症中心。进行了坏死，炎症，分级和有丝分裂的病理学评估。通过免疫组织化学检测Ki-67，PD-L1表达和肿瘤浸润淋巴细胞。如果有的话，对化疗后的同一对配对样品进行分析。病理特征和临床特征与总体生存率相关。结果分别在93和65个化学阳性MPM样品中评估了TME和PD-L1表达。28个样本的肿瘤组织不足以表达PD-L1。肉瘤样/双相性样品的特征是肿瘤细胞上的CD8 + T淋巴细胞和PD-L1表达更高，而上皮样细胞的肿瘤周围CD4 + T和CD20 + B淋巴细胞更高。较高的CD8 + T淋巴细胞，CD68 +巨噬细胞和PD-L1表达与侵袭性的病理特征（坏死，分级，Ki-67）相关。在单因素分析中，以CD8 ​​+ T浸润率较高为特征的MPM病例对化疗的反应较低，生存期较差。根据包括CD8 + T淋巴细胞，坏死，有丝分裂和增殖指数的综合评分对患者进行分层显示，中位总生存期为11.3个月，而16个月为16。高分与低分综合评分（P <0.003）的情况为4个月。在化学疗法前后对15个配对样本进行的亚组探索性分析显示，MPM样本中的细胞毒性T淋巴细胞显着增加，免疫细胞中PD-L1表达显着增加。结论富含细胞毒性T淋巴细胞的TME与肿瘤细胞上的巨噬细胞和PD-L1表达水平升高，侵袭性组织病理学特征，对化学疗法的响应较低，生存期较短有关。化学疗法作为肿瘤免疫原性诱导剂的作用应在更大的验证范围内得到证实。结论富含细胞毒性T淋巴细胞的TME与肿瘤细胞上的巨噬细胞和PD-L1表达水平升高，侵袭性组织病理学特征，对化学疗法的响应较低，生存期较短有关。化学疗法作为肿瘤免疫原性诱导剂的作用应在更大的验证范围内得到证实。结论富含细胞毒性T淋巴细胞的TME与肿瘤细胞上的巨噬细胞和PD-L1表达水平升高，侵袭性组织病理学特征，对化学疗法的响应较低，生存期较短有关。化学疗法作为肿瘤免疫原性诱导剂的作用应在更大的验证范围内得到证实。