Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells
Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells
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DOI：
10.3390/vaccines7040149
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发表时间：
2019-12-01
期刊：
影响因子：
7.8
通讯作者：
Elkord, Eyad
中科院分区：
文献类型：
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作者：
Saleh, Reem;Toor, Salman M.;Elkord, Eyad
三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，并且它对常见的乳腺癌疗法表现出抗性。靶向程序性细胞死亡1（PD-1）及其配体PD-L1的免疫检查点抑制剂（ICI）已被批准用于治疗各种癌症。然而，靶向PD-1/PD-L1轴在乳腺癌中的治疗效果正在临床研究中。此外，靶向PD-1和PD-L1的药物的作用机制尚未完全阐明。在这项研究中，我们使用共培养系统研究了人TNBC细胞系MDA-MB-231和MDA-MB-468以及非TNBC细胞系MCF-7对CD 4（+）T细胞亚群（包括调节性T细胞（TCFs））上免疫检查点（IC）表达的影响。我们还检查了单独和联合阻断PD-1或PD-L1对CD 4（+）T细胞亚群IC表达的影响。我们发现乳腺癌细胞上调了CD 4（+）T细胞亚群中的IC包括PD-1、细胞毒性T淋巴细胞相关抗原-4（CTLA-4）、T细胞免疫球蛋白和含粘蛋白结构域蛋白3（TIM-3）和淋巴细胞活化基因-3（LAG-3）的表达。我们还发现，在TNBC细胞存在的情况下，PD-1和PD-L1的共阻断进一步上调CD 4（+）CD 25（+）T细胞和CD 4（+）CD 25（+）FoxP 3（+）Helios（+）上TIM-3和LAG-3的共表达。在非TNBC细胞中。我们的研究结果表明，出现了补偿性抑制机制，最有可能是由Tcl 3和活化的非Tcl 3介导的，这可能导致TNBC对PD-1/PD-L1阻断的耐药性的发展。
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and it exhibits resistance to common breast cancer therapies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and its ligand, PD-L1, have been approved to treat various cancers. However, the therapeutic efficacy of targeting PD-1/PD-L1 axis in breast cancer is under clinical investigation. In addition, the mechanisms of action of drugs targeting PD-1 and PD-L1 have not been fully elucidated. In this study, we investigated the effect of human TNBC cell lines, MDA-MB-231 and MDA-MB-468, and the non-TNBC cell line, MCF-7, on the expression of immune checkpoints (ICs) on CD4(+) T cell subsets, including regulatory T cells (Tregs), using a co-culture system. We also examined the effect of blocking PD-1 or PD-L1 separately and in combination on IC expression by CD4(+) T cell subsets. We found that breast cancer cells upregulate the expression of ICs including PD-1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) in CD4(+) T cell subsets. We also found that the co-blockade of PD-1 and PD-L1 further upregulates the co-expression of TIM-3 and LAG-3 on CD4(+)CD25(+) T cells and CD4(+)CD25(+)FoxP3(+)Helios(+) Tregs in the presence of TNBC cells, but not in non-TNBC cells. Our results indicate the emergence of compensatory inhibitory mechanisms, most likely mediated by Tregs and activated non-Tregs, which could lead to the development of TNBC resistance against PD-1/PD-L1 blockade.