CDK4/6 抑制剂在 HR/HER2 转移性乳腺癌患者中的免疫效应：免疫抑制缓解与临床反应相关。
Immune effects of CDK4/6 inhibitors in patients with HR/HER2 metastatic breast cancer: Relief from immunosuppression is associated with clinical response.
机构信息
Department of Experimental Medicine, Laboratory of Tumor Immunology and Cell Therapy, Sapienza University of Rome, Rome 00161, Italy.
Department of Medical and Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome 00185, Italy.
出版信息
EBioMedicine. 2022 May;79:104010. doi: 10.1016/j.ebiom.2022.104010. Epub 2022 Apr 25.
BACKGROUND
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are innovative small target molecules that, in combination with endocrine therapy, have recently been employed in the treatment of patients with HR/HER2 metastatic breast cancer (mBC). In this prospective study, we investigate the impact of CDK4/6i on the immune profile of patients with HR/HER2 mBC.
METHODS
Immune cell subsets were analysed using flow cytometry of peripheral blood mononuclear cells (PBMCs) isolated from patients with HR/HER2 mBC, both before and during treatment. Regulatory T cells (Tregs) were identified using the markers CD4, CD25, CTLA4, CD45RA, and intracellular FOXP3. Monocytic and polymorphonuclear myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs) and other immune populations were analysed using CD45, CD14, CD66b, CD11c, HLA-DR, CD3, CD8, CD28, CD137, PD1, CD45RA, CCR7, and Ki67.
FINDINGS
The percentage of circulating Tregs and M/PMN-MDSCs was significantly downregulated from baseline during CDK4/6i-treatment (p<0.0001 and p<0.05, respectively). In particular, the effector Treg subset (CD4CD25FOXP3CD45RA) was strongly reduced (p<0.0001). The decrease in Treg levels was significantly greater in responder patients than in non-responder patients. Conversely, CDK4/6i treatment was associated with increased levels of CD4 T cells and anti-tumour CD137CD8 T cells (p<0.05).
INTERPRETATION
CDK4/6i treatment results in downregulation of Tregs, M-MDSCs, and PMN-MDSCs, thus weakening tumour immunosuppression. This decrease is associated with response to treatment, highlighting the importance of unleashing immunity in cancer treatment efficacy. These results suggest a novel mechanism of immunomodulation in mBC and provide valuable information for the future design of novel treatments combining CDK4/6i with immunotherapy in other cancer settings.
FUNDING
Sapienza University of Rome.
背景
细胞周期蛋白依赖性激酶 4/6 抑制剂（CDK4/6i）是一种创新的小分子靶向药物，最近已与内分泌治疗联合应用于治疗 HR/HER2 转移性乳腺癌（mBC）患者。在这项前瞻性研究中，我们研究了 CDK4/6i 对 HR/HER2 mBC 患者免疫谱的影响。
方法
使用流式细胞术分析从 HR/HER2 mBC 患者外周血单核细胞（PBMCs）中分离的免疫细胞亚群，分别在治疗前和治疗期间进行分析。使用 CD4、CD25、CTLA4、CD45RA 和细胞内 FOXP3 标记物鉴定调节性 T 细胞（Tregs）。使用 CD45、CD14、CD66b、CD11c、HLA-DR、CD3、CD8、CD28、CD137、PD1、CD45RA、CCR7 和 Ki67 分析单核细胞和多形核髓源性抑制细胞（M-MDSCs 和 PMN-MDSCs）和其他免疫细胞群。
结果
与基线相比，CDK4/6i 治疗期间循环 Tregs 和 M/PMN-MDSCs 的百分比显著下调（p<0.0001 和 p<0.05）。特别是，效应性 Treg 亚群（CD4CD25FOXP3CD45RA）明显减少（p<0.0001）。在应答患者中，Treg 水平的下降明显大于非应答患者。相反，CDK4/6i 治疗与 CD4 T 细胞和抗肿瘤 CD137CD8 T 细胞水平升高相关（p<0.05）。
结论
CDK4/6i 治疗导致 Tregs、M-MDSCs 和 PMN-MDSCs 下调，从而削弱肿瘤免疫抑制。这种减少与治疗反应相关，突出了在癌症治疗疗效中释放免疫的重要性。这些结果表明了 mBC 中免疫调节的新机制，并为未来设计将 CDK4/6i 与免疫疗法联合用于其他癌症环境中的新型治疗提供了有价值的信息。
资助
罗马萨皮恩扎大学。
Zotero 插件