联合口服低剂量环磷酰胺内分泌治疗可能通过 TLSs 中的 Tregs 改善转移性乳腺癌患者的临床反应。

Combined oral low-dose cyclophosphamide endocrine therapy may improve clinical response among patients with metastatic breast cancer via Tregs in TLSs.

机构信息

Department of Medical Oncology, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, 10 Tieyi Rd, Beijing, 100038, China.

Breast Department, Capital Medical University Cancer Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.

出版信息

Sci Rep. 2024 Jun 11;14(1):13432. doi: 10.1038/s41598-024-64042-3.

DOI:10.1038/s41598-024-64042-3

PMID:38862586

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11166640/

Abstract

Despite limited research on refractory and/or endocrine therapy failure in elderly metastatic breast cancer (MBC) patients, a prior study showed that low-dose oral cyclophosphamide (CY) can improve the overall survival rate of MBC patients, possibly through the immunoregulation of regulatory T cells (Tregs). We preliminarily investigated the combination of endocrine therapy (ET) with oral low-dose CY as salvage therapy in elderly patients via peripheral blood regulatory T-cell analyses. In addition, we evaluated the associations of tumor tertiary lymphoid structures (TLSs) with therapeutic outcomes. HR+/HER2- advanced breast cancer patients who received low-dose CY combined with ET or ET only from April 2015 to August 2021 were enrolled in this retrospective study. The primary outcome was the clinical control rate (CCR), and the secondary outcome was progression-free survival (PFS). Circulating T lymphocyte subpopulations represented by Tregs were monitored during treatment by flow cytometry methods. TLSs wereconfirmed by hematoxylin-eosin staining of pretreatment specimens, and CD3, CD4, and Foxp3 were detected using Opal multicolor immunofluorescence. A total of 85 patients who received CY + ET and 50 patients who received ET only were enrolled, the percentage of patients who received CCR was 73% (62/85) vs. 70% (45/50), and the objective response rate (ORR) was 28% (24/85) vs. 24% (12/50). No deaths occurred during the study period. The mean PFS time was 13 vs. 11 months (P = 0.03). In the CY + ET group, decreases in CD4+/CD25+/Foxp3+ T cells (P < 0.001) were favorable for both clinical control and prolonged PFS (P < 0.001). Compared with patients without TLSs, those with TLSs were more likely to have better clinical control and PFS (mean time = 6 months), and a greater number of Treg cells during TLS pretreatment correlated with longer PFS (P = 0.043). Oral low-dose CY combined with standard ET exerts immunological effects by decreasing Treg levels to achieve improved clinical responses. Moreover, patients with TLSs might benefit more from such therapy than those without TLSs, and a high Treg cell count in TLSs before treatment predicts better therapeutic efficacy.

摘要

尽管针对老年转移性乳腺癌（MBC）患者的难治性和/或内分泌治疗失败的研究有限，但先前的一项研究表明，低剂量口服环磷酰胺（CY）可提高 MBC 患者的总生存率，这可能是通过调节性 T 细胞（Tregs）的免疫调节。我们初步通过外周血调节性 T 细胞分析研究了内分泌治疗（ET）联合口服低剂量 CY 作为老年患者的挽救治疗。此外，我们评估了肿瘤三级淋巴结构（TLSs）与治疗结果的关系。本回顾性研究纳入了 2015 年 4 月至 2021 年 8 月期间接受低剂量 CY 联合 ET 或仅 ET 治疗的 HR+/HER2-晚期乳腺癌患者。主要结局是临床控制率（CCR），次要结局是无进展生存期（PFS）。通过流式细胞术方法监测治疗期间以 Tregs 为代表的循环 T 淋巴细胞亚群。使用 Opal 多色免疫荧光法检测预处理标本中的苏木精-伊红染色确认 TLSs，并检测 CD3、CD4 和 Foxp3。共纳入 85 例接受 CY+ET 治疗的患者和 50 例仅接受 ET 治疗的患者，接受 CCR 的患者比例分别为 73%（62/85）和 70%（45/50），客观缓解率（ORR）分别为 28%（24/85）和 24%（12/50）。研究期间无死亡。平均 PFS 时间为 13 个月 vs. 11 个月（P=0.03）。在 CY+ET 组中，CD4+/CD25+/Foxp3+T 细胞减少（P<0.001）有利于临床控制和延长 PFS（P<0.001）。与无 TLSs 的患者相比，有 TLSs 的患者更有可能获得更好的临床控制和 PFS（平均时间为 6 个月），且 TLS 预处理时 Treg 细胞数量较多与更长的 PFS 相关（P=0.043）。口服低剂量 CY 联合标准 ET 通过降低 Treg 水平发挥免疫作用，从而实现更好的临床反应。此外，与无 TLSs 的患者相比，有 TLSs 的患者可能从这种治疗中获益更多，且 TLS 治疗前 Treg 细胞计数较高预示着更好的治疗效果。