Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature
Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature
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通过 CD276 靶向光动力消融肿瘤细胞和肿瘤脉管系统增强抗 PD-1/PD-L1 免疫检查点抑制性癌症治疗
DOI：
10.1021/acs.molpharmaceut.8b00997
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发表时间：
2019-01-01
影响因子：
4.9
通讯作者：
Liu, Zhaofei
中科院分区：
文献类型：
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作者：
Bao, Rui;Wang, Yanpu;Liu, Zhaofei
已证明抗血管生成疗法通过克服肿瘤微环境的免疫抑制状态来改善免疫检查点抑制的功效。然而，目前大多数抗血管生成剂不能区分肿瘤血管生成和生理性血管生成。本研究的目的是研究靶向CD 276（一种在各种肿瘤细胞和肿瘤血管系统中过表达但在正常组织血管系统中表达有限的受体）的光动力治疗（PDT）药物是否可以改善PD-1/PD-L1阻断剂的肿瘤抑制功效。通过将抗CD 276抗体的Fab片段与光敏剂IRDye 700缀合来合成CD 276靶向剂（IRD-aCD 276/Fab）。在皮下和肺转移性肿瘤模型中测试IRD-α CD 276/Fab在有或没有抗PD-1/PD-L1阻断的情况下的体内肿瘤靶向功效和治疗效果。IRD-α CD 276/Fab的PDT显著抑制皮下4 T1肿瘤的生长并抑制其肺转移。此外，它通过增加树突状细胞的活化和成熟来触发体内抗肿瘤免疫。在使用IRD-α CD 276/Fab的PDT后，肿瘤PD-L1水平也显著增加，如通过非侵入性PD-L1靶向小动物PET成像所证明的。与抗PD-1/PD-L1阻断剂联合使用时，IRD-α CD 276/Fab PDT可显著抑制肿瘤生长，并通过募集CD 8（+）T细胞的肿瘤浸润来防止其转移至肺。我们的数据为靶向CD 276的PDT在局部免疫调节中的作用提供了证据，并且其与PD-L1/PD-1轴抑制的组合是通过产生局部和全身抗肿瘤应答来消除原发性肿瘤以及播散性转移的有希望的策略。
Antiangiogenic therapies have been demonstrated to improve the efficacy of immune checkpoint inhibition by overcoming the immunosuppressive status of the tumor microenvironment. However, most of the current antiangiogenic agents cannot discriminate tumor angiogenesis from physiological angiogenesis. The aim of this study was to investigate whether a photodynamic therapy (PDT) agent that targets CD276, a receptor overexpressed in various tumor cells and tumor vasculature but with limited expression in normal tissue vasculature, could improve the tumor inhibitory efficacy of a PD-1/PD-L1 blockade. A CD276-targeting agent (IRD-alpha CD276/Fab) was synthesized by conjugating the Fab fragment of an anti-CD276 antibody with a photosensitizer IRDye700. The in vivo tumor-targeting efficacy and therapeutic effects of IRD-alpha CD276/Fab with or without an anti-PD-1/PD-L1 blockade were tested in subcutaneous and lung metastatic tumor models. PDT using IRD-alpha CD276/Fab significantly suppressed the growth of subcutaneous 4T1 tumor and inhibited its lung metastasis. Moreover, it triggered in vivo antitumor immunity by increasing the activation and maturation of dendritic cells. Tumor PD-L1 levels were also markedly increased after PDT using IRD-alpha CD276/Fab, as evidenced by noninvasive PD-Ll-targeted small-animal PET imaging. In combination with an anti-PD-1/PD-L1 blockade, IRD-alpha CD276/Fab PDT markedly suppressed the growth of tumors and prevented their metastasis to the lung by recruiting the tumor infiltration of CD8(+) T cells. Our data provide evidence for the role of CD276-targeted PDT for local immune modulation, and its combination with PD-L1/PD-1 axis inhibition is a promising strategy for eliminating primary tumors as well as disseminated metastases, by generating local and systemic antitumor responses.