肿瘤细胞源性乳酸抑制PD-L1蛋白和PD-L1抗体在PD-L1/PD-1阻断治疗耐药肿瘤中的相互作用

Wonkyung Oh, A. Kim, D. Dhawan, D. Knapp, Seung-Oe Lim
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引用次数: 0

摘要

针对PD-1/PD-L1轴的免疫检查点阻断疗法在多种癌症类型中显示出显着的临床效果。然而,尽管最近PD-1/PD-L1阻断疗法取得了成功,但癌症患者的这种反应率仅限于包含特定肿瘤微环境特征的肿瘤。癌细胞代谢活性的改变通过影响免疫细胞的活性来形成抗肿瘤免疫反应。然而,癌细胞代谢活性的改变如何影响其对PD-1/PD-L1阻断治疗的耐药性,目前尚不清楚。在这里,我们发现肿瘤细胞来源的乳酸通过抑制PD-L1蛋白和抗PD-L1抗体之间的相互作用,在PD-1/PD-L1阻断抵抗肿瘤中产生免疫抑制肿瘤微环境。此外,我们发现针对PD-L1的PD-L1抗体-药物偶联物(PD-L1- adc)和减少乳酸与MCT-1抑制剂AZD3965的联合治疗可以有效治疗PD-1/PD-L1阻断耐药的肿瘤。本研究的发现提供了乳酸诱导免疫抑制环境的新机制,并提出了克服PD-1/PD-L1阻断治疗耐药的潜在联合治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Tumor cell-derived lactic acid inhibits the interaction of PD-L1 protein and PD-L1 antibody in the PD-L1/PD-1 blockade therapy-resistant tumor
Immune checkpoint blockade therapy targeting the PD-1/PD-L1 axis has shown remarkable clinical impact in multiple cancer types. Nontheless, despite the recent success of PD-1/PD-L1 blockade therapy, such response rates in cancer patients have been limited to tumors encompassing specific tumor microenvironment characteristics. The altered metabolic activity of cancer cells shapes the anti-tumor immune response by affecting the activity of immune cells. However, it remains mostly unknown how the altered metabolic activity of cancer cells impacts their resistance to PD-1/PD-L1 blockade therapy. Here we found that tumor cell-derived lactic acid renders the immunosuppressive tumor microenvironment in the PD-1/PD-L1 blockade-resistant tumors by inhibiting the interaction between the PD-L1 protein and anti-PD-L1 antibody. Furthermore, we showed that the combination therapy of targeting PD-L1 with our PD-L1 antibody-drug conjugate (PD-L1-ADC) and reducing lactic acid with the MCT-1 inhibitor, AZD3965, can effectively treat the PD-1/PD-L1 blockade resistant tumors. The findings in this study provide a new mechanism of how lactic acid induces an immunosuppressive environment and suggest a potential combination treatment to overcome the PD-1/PD-L1 blockade therapy resistance.
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