Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities.
Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1/PD-L1 Pathways: Challenges and Opportunities.
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DOI：
10.3389/fimmu.2020.598877
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Hack SP;Zhu AX;Wang Y
使用靶向程序性细胞死亡1蛋白（PD-1）/程序性细胞死亡1配体1（PD-L1）轴的抗体的癌症免疫疗法（CIT）改变了多种癌症的护理标准。然而，仅在少数患者中观察到持久的抗肿瘤反应，表明存在其他抑制机制，可抑制抗癌免疫。因此，需要靶向其他免疫抑制机制的新治疗策略，以增强抗癌免疫力，并在免疫检查点抑制耐药患者中最大限度地发挥CIT的临床获益。临床前和临床研究已经确定了肿瘤微环境（TME）的异常，这些异常可能对PD-1/PD-L1阻断的疗效产生负面影响。血管生成因子如血管内皮生长因子（VEGF）通过诱导血管异常、抑制抗原呈递和免疫效应细胞或增强调节性T细胞、骨髓源性抑制细胞和肿瘤相关巨噬细胞的免疫抑制活性来驱动TME中的免疫抑制。反过来，免疫抑制细胞可以驱动血管生成，从而产生抑制抗肿瘤免疫的恶性循环。TME中VEGF介导的免疫抑制及其对CIT疗效的负面影响提供了将联合收割机PD-1/PD-L1抗体与抗VEGF药物组合以使TME正常化的治疗原理。已经启动了大量临床试验以评估PD-1/PD-L1抗体与抗VEGF抗体在多种癌症中的组合。最近，在非小细胞肺癌（腺癌）、肾细胞癌和肝细胞癌中进行的五项III期研究的阳性结果表明，与各自的护理标准相比，PD-1/PD-L1抗体和抗VEGF药物的组合显著改善了临床结局。这种组合已被卫生当局批准，现在是肾细胞癌、非小细胞肺癌和肝细胞癌的标准治疗选择。目前正在进行大量其他类似组合的随机研究。在这里，我们讨论了VEGF介导的免疫抑制的临床前模型或转化临床研究的一部分研究的原则机制。我们还讨论了最近报道的随机临床试验的数据。最后，我们讨论了如何将这些概念和方法进一步纳入临床实践，以改善癌症患者的免疫治疗结果。
Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.
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影响因子：
6.4
作者：
Chang, Chun-Jung;Yang, Yao-Hsu;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
17.1
作者：
Allen E;Jabouille A;Rivera LB;Lodewijckx I;Missiaen R;Steri V;Feyen K;Tawney J;Hanahan D;Michael IP;Bergers G
通讯作者：
Bergers G
影响因子：
4.4
作者：
Bouzin, Caroline;Brouet, Agnes;Feron, Olivier
通讯作者：
Feron, Olivier
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
8.8
作者：
Alfaro, C.;Suarez, N.;Gonzalez, A.;Solano, S.;Erro, L.;Dubrot, J.;Palazon, A.;Hervas-Stubbs, S.;Gurpide, A.;Lopez-Picazo, J. M.;Grande-Pulido, E.;Melero, I.;Perez-Gracia, J. L.
通讯作者：
Perez-Gracia, J. L.