Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy.
Anti-PD-1 antibody significantly increases therapeutic efficacy of Listeria monocytogenes (Lm)-LLO immunotherapy.
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DOI：
10.1186/2051-1426-1-15
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发表时间：
2013
影响因子：
10.9
通讯作者：
Khleif SN
中科院分区：
文献类型：
--
作者：
Mkrtichyan M;Chong N;Abu Eid R;Wallecha A;Singh R;Rothman J;Khleif SN
肿瘤免疫逃逸机制和成功免疫治疗的重要障碍之一是肿瘤通过细胞间或受体/配体相互作用介导的免疫反应抑制。程序性死亡受体-1 （PD-1）与其配体PD-L1和PD-L2的相互作用是许多肿瘤逃避免疫监视的重要策略之一。当PD-Ls与PD-1结合时，T细胞受体（TCR）信号被抑制，导致增殖抑制、细胞因子产生减少、能量减少和/或细胞凋亡。因此，肿瘤细胞表达PD-Ls作为一种保护机制，导致肿瘤微环境中肿瘤浸润淋巴细胞受到抑制。Lm-LLO免疫疗法已被证明具有治疗效果，因为它们能够诱导有效的抗原特异性免疫反应。然而，已有研究表明，感染Lm可导致小鼠免疫细胞上PD-L1的上调，从而通过PD-1/PD-L1途径抑制效应T细胞。在E7抗原表达的TC-1小鼠肿瘤模型中，检测李斯特菌疫苗（Lm-LLO-E7）联合抗pd -1抗体的治疗效果和免疫效果。评估免疫治疗后肿瘤生长、存活以及周围和肿瘤浸润性免疫细胞谱。本研究表明，Lm-LLO免疫疗法与阻断PD-1/PD-L1相互作用的抗PD-1抗体联合使用，可显著提高TC-1小鼠肿瘤模型的免疫和治疗效果。重要的是，我们发现除了由Lm-LLO免疫疗法介导的脾脏和肿瘤微环境中的调节性T细胞（Treg）和髓源性抑制细胞（MDSC）的显著减少外，在治疗中加入抗pd -1抗体导致肿瘤周围抗原特异性免疫反应和CD8 T细胞浸润的显著增加。因此，这种联合治疗可以显著抑制肿瘤生长，延长治疗动物的生存期/肿瘤完全消退。我们还证明，体外感染Lm会导致人单核细胞来源的树突状细胞表面PD-L1表达显著上调，这表明这一发现具有翻译能力。我们的研究结果表明，基于lm - llo的疫苗与阻断PD-1/PD-L1相互作用的结合是一种可行的方法，具有临床转化潜力，可以全面提高抗肿瘤免疫治疗的疗效。
One of the significant tumor immune escape mechanisms and substantial barrier for successful immunotherapy is tumor-mediated inhibition of immune response through cell-to-cell or receptor/ligand interactions. Programmed death receptor-1 (PD-1) interaction with its ligands, PD-L1 and PD-L2, is one of the important strategies that many tumors employ to escape immune surveillance. Upon PD-Ls binding to PD-1, T cell receptor (TCR) signaling is dampened, causing inhibition of proliferation, decreased cytokine production, anergy and/or apoptosis. Thus PD-Ls expression by tumor cells serves as a protective mechanism, leading to suppression of tumor-infiltrating lymphocytes in the tumor microenvironment. Lm-LLO immunotherapies have been shown to be therapeutically effective due to their ability to induce potent antigen-specific immune responses. However, it has been demonstrated that infection with Lm leads to up-regulation of PD-L1 on mouse immune cells that can inhibit effector T cells through PD-1/PD-L1 pathway. Therapeutic and immune efficacy of Listeria-based vaccine (Lm-LLO-E7) in combination with anti-PD-1 antibody was tested in E7 antigen expressing TC-1 mouse tumor model. Tumor growth, survival, as well as peripheral and tumor-infiltrating immune cell profiles after immunotherapy were assessed. Here we demonstrate that the combination of an Lm-LLO immunotherapy with anti-PD-1 antibody that blocks PD-1/PD-L1 interaction, significantly improves immune and therapeutic efficacy of treatment in TC-1 mouse tumor model. Importantly, we show that in addition to significant reduction of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) in both spleen and tumor microenvironment that are mediated solely by the Lm-LLO immunotherapy, the addition of anti-PD-1 antibody to the treatment results in significant increase of antigen-specific immune responses in periphery and CD8 T cell infiltration into the tumor. As a result, this combinational treatment leads to significant inhibition of tumor growth and prolonged survival/complete regression of tumors in treated animals. We also demonstrate that in vitro infection with Lm results in significant upregulation of surface PD-L1 expression on human monocyte-derived dendritic cells suggesting the translational capacity of this finding. Our findings demonstrate that combination of Lm-LLO-based vaccine with blocking of PD-1/PD-L1 interaction is a feasible approach with clinical translation potential that can lead to overall enhancement of the efficacy of anti-tumor immunotherapy.