Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer.
Improved T-cell Immunity Following Neoadjuvant Chemotherapy in Ovarian Cancer.
复制标题
卵巢癌新辅助化疗后T细胞免疫功能的改善
DOI：
10.1158/1078-0432.ccr-21-2834
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发表时间：
2022-08-02
影响因子：
11.5
通讯作者：
Konstantinopoulos, Panagiotis A.
中科院分区：
文献类型：
--
作者：
Liu, Min;Tayob, Nabihah;Penter, Livius;Sellars, MacLean;Tarren, Anna;Chea, Vipheaviny;Carulli, Isabel;Huang, Teddy;Li, Shuqiang;Cheng, Su-Chun;Le, Phuong;Frackiewicz, Laura;Fasse, Julia;Qi, Courtney;Liu, Joyce F.;Stover, Elizabeth H.;Curtis, Jennifer;Livak, Kenneth J.;Neuberg, Donna;Zhang, Guanglan;Matulonis, Ursula A.;Wu, Catherine J.;Keskin, Derin B.;Konstantinopoulos, Panagiotis A.
尽管基于局部组织的免疫反应对于阐明肿瘤-免疫细胞的直接相互作用至关重要，但人们越来越认识到外周免疫反应在抗癌免疫中发挥着重要作用。我们评估了接受标准护理新辅助卡铂和紫杉醇化疗（包括用于预防紫杉醇相关超敏反应的地塞米松）的晚期上皮性卵巢癌（EOC）患者的连续血液样本，以表征整个治疗过程中外周免疫细胞功能和组成的演变。收集 10 名接受新辅助化疗 (NACT) 治疗的晚期高级别浆液性卵巢癌患者在化疗开始前、第三个和第六个周期后以及化疗完成后约 2 个月的连续血样。使用离体 IFNγ ELISpot 测定评估 T 细胞功能，并使用批量和单细胞 RNA 测序 (RNAseq) 评估 T 细胞库和免疫细胞组成的动态。 NACT 后，T 细胞对病毒抗原的反应有所改善，这与 CA125 水平的下降相一致。单细胞分析显示，化疗期间记忆 T 细胞受体 (TCR) 克隆型数量增加，中央记忆 CD8+ 和调节性 T 细胞增加。最后，NACT 的施用与单核细胞频率以及 HLA II 类和抗原呈递基因表达的增加有关。单细胞 RNAseq 分析表明，尽管主要由经典单核细胞驱动，但化疗后在单核细胞亚群中观察到 II 类基因表达增加的一个特征。 NACT 可以通过减少肿瘤负荷来减轻肿瘤相关的免疫抑制，并可以增强抗原的加工和呈递。这些发现对于免疫检查点阻断和治疗性疫苗方法在 EOC 中的成功组合应用具有重要意义。
Although local tissue-based immune responses are critical for elucidating direct tumor–immune cell interactions, peripheral immune responses are increasingly recognized as occupying an important role in anticancer immunity. We evaluated serial blood samples from patients with advanced epithelial ovarian cancer (EOC) undergoing standard-of-care neoadjuvant carboplatin and paclitaxel chemotherapy (including dexamethasone for prophylaxis of paclitaxel-associated hypersensitivity reactions) to characterize the evolution of the peripheral immune cell function and composition across the course of therapy. Serial blood samples from 10 patients with advanced high-grade serous ovarian cancer treated with neoadjuvant chemotherapy (NACT) were collected before the initiation of chemotherapy, after the third and sixth cycles, and approximately 2 months after completion of chemotherapy. T-cell function was evaluated using ex vivo IFNγ ELISpot assays, and the dynamics of T-cell repertoire and immune cell composition were assessed using bulk and single-cell RNA sequencing (RNAseq). T cells exhibited an improved response to viral antigens after NACT, which paralleled the decrease in CA125 levels. Single-cell analysis revealed increased numbers of memory T-cell receptor (TCR) clonotypes and increased central memory CD8+ and regulatory T cells throughout chemotherapy. Finally, administration of NACT was associated with increased monocyte frequency and expression of HLA class II and antigen presentation genes; single-cell RNAseq analyses showed that although driven largely by classical monocytes, increased class II gene expression was a feature observed across monocyte subpopulations after chemotherapy. NACT may alleviate tumor-associated immunosuppression by reducing tumor burden and may enhance antigen processing and presentation. These findings have implications for the successful combinatorial applications of immune checkpoint blockade and therapeutic vaccine approaches in EOC.