Abstract：
Breast cancer (BC) is the most prevalent diagnosed cancer among women. Herceptin blocks the effects of Her-2 and tumour cell growth. Despite many achievements using Herceptin in Her-2+ invasive BC treatment, there are treatment failures and resistances. The signal transducer and activator of transcription 3 (STAT3) is persistently activated in BC and is associated with immune suppression and tumour cell proliferation. We evaluated whether STAT3 inhibition could increase Herceptin impact on in vitro reduction of immune checkpoint inhibitors and polarize T cells to a protective immune response. We treated SK-BR-3 cells with Herceptin and the STAT3-inhibitor (FLLL32) and assessed the apoptosis and expression of apoptosis-related proteins, VEGF, Her-2 and apoptosis targets of STAT3. PBMCs were isolated from healthy donors and co-cultured with SK-BR-3 cells in the presence or absence of Herceptin and FLLL32. PD-L1, CTLA-4, TIM-3 and T-cell intracellular cytokines were then evaluated. Our results demonstrated that STAT3 inhibition and Herceptin increased SK-BR-3 cell apoptosis, significantly. STAT3 inhibition through combination treatment had a more significant effect on regulating PD-1, TIM-3 and CTLA-4 expression on PBMCs. Alternatively, the combination of FLLL32 and Herceptin promoted T helper-1 protective immune response. The combination of FLLL32 and Herceptin suppress the expression of immune checkpoints and provoke the T-helper1 immune response in lymphocytes. Our analysis indicates STAT3 as a promising target that improves Herceptin\'s role in breast cancer cell apoptosis.
摘要：
乳腺癌（BC）是女性中最常见的癌症。赫赛汀阻断Her-2和肿瘤细胞生长的作用。尽管在Her-2+侵袭性BC治疗中使用赫赛汀取得了许多成就，有治疗失败和阻力。信号转导和转录激活因子3（STAT3）在BC中持续激活，并与免疫抑制和肿瘤细胞增殖有关。我们评估了STAT3抑制是否可以增加赫赛汀对免疫检查点抑制剂体外减少的影响，并将T细胞极化为保护性免疫应答。我们用赫赛汀和STAT3抑制剂（FLLL32）处理SK-BR-3细胞，并评估凋亡和凋亡相关蛋白的表达。VEGF,Her-2和STAT3的凋亡目标。从健康供体分离PBMC,并在存在或不存在赫赛汀和FLLL32的情况下与SK-BR-3细胞共培养。然后评估PD-L1、CTLA-4、TIM-3和T细胞胞内细胞因子。我们的结果表明，抑制STAT3和赫赛汀增加SK-BR-3细胞凋亡，显著。通过组合治疗的STAT3抑制对调节PBMC上的PD-1、TIM-3和CTLA-4表达具有更显著的作用。或者，FLLL32和赫赛汀的组合可促进T辅助-1保护性免疫应答。FLLL32和赫赛汀的组合抑制免疫检查点的表达并激发淋巴细胞中的T-helper1免疫应答。我们的分析表明，STAT3是一个有希望的靶标，可以改善赫赛汀在乳腺癌细胞凋亡中的作用。
