目的:最近证明免疫检查点抑制剂对晚期和复发性子宫内膜癌患者有益。这项回顾性研究调查了子宫内膜癌的免疫检查点分子,因为它们与分子亚型有关。临床结果,和预测价值。
方法:控制免疫检查点的基因的肿瘤RNA表达,程序性细胞死亡1(PD1,由PDCD1编码),其配体(PDL1,由CD274编码),通过定量聚合酶链反应(qPCR)在239例子宫内膜癌组织中测定了干扰素γ(IFNG),并与25例对照的子宫内膜组织进行了比较。共81个子宫内膜癌组织使用ProMiSe分子分类进行分析,并分析了整个队列的患者轨迹.研究结果在来自癌症基因组图谱(TCGA;n=548)的独立队列中得到验证。
结果:与非恶性对照组织相比,子宫内膜癌中PD1、PDL1和IFNG的表达明显更高,对照组织中的平均表达为0.12、0.05和0.05,子宫内膜癌中的平均表达为0.44、0.31和0.35。分别。POLE突变和错配修复缺陷(MMRd)(免疫热)肿瘤显示PD1和IFNG的最高表达。PD1、PDL1和IFNG的表达增加与无复发改善相关(分别为HR0.32,p<0.001;HR0.30,p<0.001;HR0.47,p=0.012),疾病特异性(分别为HR0.38,p<0.001;HR0.29,p<0.001;HR0.45,p=0.017),和总生存期(分别为HR0.56,p=0.003;HR0.38,p<0.001;HR0.58,p=0.006)。Cox回归证实了PD1对无复发生存率(HR0.39,p=0.009)和PDL1对总生存率(HR0.55,p=0.037)的预后意义。肿瘤PD1对无复发生存率的预后价值,疾病特异性生存,在TCGA队列中确认了总生存期。
结论:控制PD1免疫检查点的肿瘤基因表达,特别是在“热肿瘤”中表达,预测无复发,疾病特异性,两个独立队列中子宫内膜癌患者的总生存期。对这些基因的评估可用于对符合免疫检查点抑制剂资格的患者进行分层,值得前瞻性临床试验。
OBJECTIVE: Immune checkpoint inhibitors have recently demonstrated benefit in patients with advanced and recurrent endometrial carcinoma. This retrospective study investigated immune checkpoint molecules in endometrial carcinoma as they pertain to the molecular subtypes, clinical outcomes, and predictive value.
METHODS: Tumoral RNA expression of genes controlling the immune checkpoint, programmed cell death 1 (PD1, encoded by PDCD1), its ligand (PDL1, encoded by CD274), and interferon gamma (IFNG) was determined in 239 endometrial carcinoma tissues by quantitative polymerase chain reaction (qPCR) and compared with endometrial tissue from 25 controls. A total of 81 endometrial carcinoma tissues were analyzed using the ProMiSe molecular classification, and patient trajectories were analyzed for the entire cohort. Findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA; n=548).
RESULTS: PD1, PDL1, and IFNG expression was significantly higher in endometrial carcinoma when compared with non-malignant control tissue with a mean expression of 0.12, 0.05, and 0.05 in control tissue and 0.44, 0.31, and 0.35 in endometrial carcinoma, respectively. POLE-mutated and mismatch repair-deficient (MMRd) (immunologically hot) tumors showed the highest expression of PD1 and IFNG. Increased expression of PD1, PDL1, and IFNG was associated with improved recurrence-free (HR 0.32, p<0.001; HR 0.30, p<0.001; HR 0.47, p=0.012, respectively), disease-specific (HR 0.38, p<0.001; HR 0.29, p<0.001; HR 0.45, p=0.017, respectively), and overall survival (HR 0.56, p=0.003; HR 0.38, p<0.001; HR 0.58, p=0.006, respectively). Cox regression confirmed the prognostic significance of PD1 for recurrence-free survival (HR 0.39, p=0.009) and PDL1 for overall survival (HR 0.55, p=0.037). The prognostic value of tumoral PD1 on recurrence-free survival, disease-specific survival, and overall survival was confirmed in the TCGA cohort.
CONCLUSIONS: Tumoral gene expression controlling the PD1 immune checkpoint, particularly expressed in \"hot tumors\", predicted recurrence-free, disease-specific, and overall survival in patients with endometrial carcinoma in two independent cohorts. Evaluation of these genes could be used to stratify patients who qualify for immune checkpoint inhibitors, which warrants prospective clinical trials.