PDF(Pubmed)
Abstract：
Treatment of advanced triple-negative breast cancer (TNBC) is a great challenge in clinical practice. The immune checkpoints are a category of immunosuppressive molecules that cancer could hijack and impede anti-tumor immunity. Targeting immune checkpoints, such as anti-programmed cell death 1 (PD-1) therapy, is a promising therapeutic strategy in TNBC. The efficacy and safety of PD-1 monoclonal antibody (mAb) with chemotherapy have been validated in TNBC patients. However, the precise mechanisms underlying the synergistic effect of chemotherapy and anti-PD-1 therapy have not been elucidated, causing the TNBC patients that might benefit from this combination regimen not to be well selected. In the present work, we found that IL-23, an immunological cytokine, is significantly upregulated after chemotherapy in TNBC cells and plays a vital role in enhancing the anti-tumor immune response of cytotoxic T cells (CTLs), especially in combination with PD-1 mAb. In addition, the combination of IL-23 and PD-1 mAb could synergistically inhibit the expression of Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), which is a regulatory subunit of PI3K and inhibit p110 activity, and promote phosphorylation of AKT in TNBC-specific CTLs. Our findings might provide a molecular marker that could be used to predict the effects of combination chemotherapy therapy and PD-1 mAb in TNBC.
摘要：
晚期三阴性乳腺癌（TNBC）的治疗在临床实践中是一个巨大的挑战。免疫检查点是一类免疫抑制分子，癌症可以劫持并阻碍抗肿瘤免疫。瞄准免疫检查站，如抗程序性细胞死亡1（PD-1）治疗，是TNBC的一种有前途的治疗策略。已在TNBC患者中验证了PD-1单克隆抗体（mAb）与化疗的有效性和安全性。然而,化疗和抗PD-1治疗协同作用的确切机制尚未阐明，导致可能从这种联合方案中受益的TNBC患者没有得到很好的选择。在目前的工作中,我们发现IL-23是一种免疫细胞因子，化疗后在TNBC细胞中显著上调，在增强细胞毒性T细胞（CTL）的抗肿瘤免疫应答中起着至关重要的作用，特别是与PD-1mAb联合使用。此外,IL-23和PD-1mAb的联合使用可以协同抑制磷酸肌醇-3激酶调节亚基1（PIK3R1）的表达，它是PI3K的调节亚基，抑制p110活性，并促进TNBC特异性CTL中AKT的磷酸化。我们的发现可能提供了一个分子标记，可用于预测联合化疗和PD-1mAb在TNBC中的作用。
