Association of Peripheral Monocytic-Myeloid-Derived Suppressor Cells with Molecular Subtypes in Single Center Endometrial Cancer Patients Receiving Carboplatin + Paclitaxel/Avelumab (MITO END-3 Trial)

The MITO-END3 trial compared carboplatin and paclitaxel (CP) with avelumab plus carboplatin and paclitaxel (CPA) as first-line treatment in endometrial cancer (EC) patients and demonstrated a significant interaction between avelumab response and mismatch repair status. To investigate prognostic/predictive biomarker, twenty-nine MITO-END3-EC patients were evaluated at pre-treatment (B1) and at the end of CP/CPA treatment (B2) for peripheral Myeloid derived suppressor cells (MDSC) and Tregs. At B2, effector Tregs frequency was significantly higher in patients treated with CPA as compared to CP (p=0.038). Both treatments (CP/CPA) induced significant decrease in peripheral M-MDSC (-5.41%) in TCGA 2-MSI-High as compared to TCGA-category 4 tumors (p=0.004). In accordance, both treatments induced M-MDSCs (+5.34%) in MSS patients as compared to MSI-High patients (p=0.001). Moreover, in a subgroup of patients, primary tumors were highly infiltrated by M-MDSCs in MSS as compared to MSI-high ECs. A post hoc analysis displayed higher frequeny of M-MDSCs (p=0.020) and lower frequency of CD4+ (p<0.005) at pretreatment in EC patients as compared to healthy donors. In conclusion, the peripheral evaluation of MDSCs and Tregs correlated with molecular features in EC treated with CP/CPA and may add insights in identifying EC patients responder to first line chemo/chemo-immunotherapy.MITO-END3试验对比了卡铂联合紫杉醇（CP方案）与阿维鲁单抗联合卡铂、紫杉醇（CPA方案）作为子宫内膜癌（endometrial cancer, EC）患者的一线治疗方案，并证实阿维鲁单抗的疗效与错配修复（mismatch repair）状态存在显著交互作用。为探究预后/预测生物标志物，研究对29例纳入MITO-END3试验的EC患者，分别在治疗前（B1节点）与CP/CPA方案治疗结束时（B2节点），对外周血髓系来源抑制细胞（Myeloid derived suppressor cells, MDSC）与调节性T细胞（Tregs）进行了检测评估。在B2节点，与CP方案组相比，CPA方案组患者的效应性调节性T细胞频率显著升高（p=0.038）。相较于癌症基因组图谱（The Cancer Genome Atlas, TCGA）4型肿瘤患者，TCGA 2型微卫星高度不稳定（Microsatellite Instability-High, MSI-High）肿瘤患者在接受两种方案（CP/CPA）治疗后，外周血单核细胞型髓系来源抑制细胞（monocytic Myeloid derived suppressor cells, M-MDSC）水平显著下降（降幅达5.41%，p=0.004）。与之相符，相较于MSI-High患者，微卫星稳定（Microsatellite Stability, MSS）患者接受两种方案治疗后，外周血M-MDSC水平升高了5.34%（p=0.001）。此外，在部分患者亚组中，相较于MSI-High型EC患者，MSS型EC患者的原发肿瘤组织中M-MDSC浸润程度更高。一项事后分析显示，与健康供者相比，子宫内膜癌患者在治疗前的外周血M-MDSC频率更高（p=0.020），而CD4+ T细胞频率更低（p<0.005）。综上，外周血MDSCs与Tregs的检测结果与接受CP/CPA方案治疗的EC患者的分子特征具有相关性，可为识别一线化疗/化疗联合免疫治疗应答的EC患者提供新的研究视角。