同期放化疗治疗宫颈癌过程中局部和全身肿瘤免疫微环境的动态变化：一项前瞻性临床试验。
The Dynamic Alternation of Local and Systemic Tumor Immune Microenvironment During Concurrent Chemoradiotherapy of Cervical Cancer: A Prospective Clinical Trial.
机构信息
Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Department of Gynecological Oncology, Guizhou Provincial People's Hospital, Guiyang, China.
出版信息
Int J Radiat Oncol Biol Phys. 2021 Aug 1;110(5):1432-1441. doi: 10.1016/j.ijrobp.2021.03.003. Epub 2021 Mar 10.
PURPOSE
This work assessed local and systemic alternations of the tumor immune microenvironment during concurrent chemoradiation therapy (CCRT) of local advanced cervical cancer to estimate the optimal timing for immune therapy in relation to CCRT.
METHODS AND MATERIALS
In this single-center prospective clinical trial, 55 patients with stage IIA through IVA cervical cancer were enrolled between December 2016 and November 2017. The median follow-up was 32.1 months. All patients received cisplatin concurrently with external beam radiation therapy combined with high-dose-rate brachytherapy. Tumor tissues and peripheral blood mononuclear cells (PBMCs) were collected before, during and after CCRT. We analyzed the changes in lymphocyte subpopulations, programmed death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, and the T cell receptor (TCR) repertoire that occurred throughout CCRT.
RESULTS
The frequencies of CD4 and PD-1 T cells in PBMCs decreased after the start of CCRT, whereas that of inhibitory regulatory T cells increased. In the tumor tissues, CCRT decreased the numbers of CD4 and CD8 T cells and reduced the median percentage of positive cells expressing PD-L1 from 78.1% to 49.8%. As indicated by the numbers of unique clones, the TCRs of PBMCs exhibited greater diversity before CCRT than after CCRT. Greater TCR diversity in PBMCs before CCRT was associated with superior 30-month progression-free survival (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.04-0.39; P = .001) and overall survival (HR, 0.17; 95% CI, 0.04-0.68; P = .004).
CONCLUSIONS
CCRT for cervical cancer altered the tumor immune microenvironment by reducing CD4 and CD8 T lymphocyte populations, PD-1/PD-L1 expression, and TCR diversity. Higher TCR diversity in PBMCs before CCRT resulted in better survival and prognosis, indicating that CCRT might inhibit immune activation. Our results suggest that it might be more effective to administer immune checkpoint inhibitors before CCRT of cervical cancer rather than during or after CCRT.
目的
本研究旨在评估局部晚期宫颈癌同期放化疗（CCRT）过程中肿瘤免疫微环境的局部和全身变化，以评估免疫治疗与 CCRT 相关的最佳时机。
方法和材料
在这项单中心前瞻性临床试验中，于 2016 年 12 月至 2017 年 11 月期间共纳入了 55 例 IIA 至 IVA 期宫颈癌患者。中位随访时间为 32.1 个月。所有患者均接受顺铂联合外照射放疗联合高剂量率近距离放疗。在 CCRT 前后采集肿瘤组织和外周血单个核细胞（PBMC）。我们分析了整个 CCRT 过程中发生的淋巴细胞亚群、程序性死亡-1（PD-1）和程序性细胞死亡配体 1（PD-L1）表达以及 T 细胞受体（TCR）谱的变化。
结果
CCRT 开始后，PBMC 中 CD4 和 PD-1 T 细胞的频率下降，而抑制性调节 T 细胞的频率增加。在肿瘤组织中，CCRT 降低了 CD4 和 CD8 T 细胞的数量，并将 PD-L1 阳性细胞的中位数百分比从 78.1%降低至 49.8%。如 PBMC 中独特克隆的数量所示，CCRT 前的 TCR 多样性大于 CCRT 后的 TCR 多样性。CCRT 前 PBMC 中更大的 TCR 多样性与更好的 30 个月无进展生存（风险比[HR]，0.12；95%置信区间[CI]，0.04-0.39；P=0.001）和总生存（HR，0.17；95%CI，0.04-0.68；P=0.004）相关。
结论
宫颈癌的 CCRT 通过减少 CD4 和 CD8 T 淋巴细胞群、PD-1/PD-L1 表达和 TCR 多样性来改变肿瘤免疫微环境。CCRT 前 PBMC 中更高的 TCR 多样性导致更好的生存和预后，表明 CCRT 可能抑制免疫激活。我们的结果表明，在宫颈癌的 CCRT 之前而不是在 CCRT 期间或之后给予免疫检查点抑制剂可能更有效。
Zotero 插件