Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.
Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy.
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DOI：
10.1158/2326-6066.cir-16-0206
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发表时间：
2017-01
影响因子：
10.1
通讯作者：
Hodi FS
中科院分区：
文献类型：
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作者：
Wu X;Giobbie-Hurder A;Liao X;Connelly C;Connolly EM;Li J;Manos MP;Lawrence D;McDermott D;Severgnini M;Zhou J;Gjini E;Lako A;Lipschitz M;Pak CJ;Abdelrahman S;Rodig S;Hodi FS
靶向CTLA-4和PD-1的免疫检查点疗法已被证明在癌症治疗中有效。然而，鉴定用于预测临床结果的生物标志物和克服耐药性的机制仍然是关键需求。血管生成作为一种免疫调节剂，具有与检查点阻断联合使用的潜力，越来越受到重视。血管生成素-2（ANGPT 2）是患者的免疫靶点，并参与对单克隆抗体贝伐单抗VEGF治疗的抵抗。我们研究了接受免疫检查点治疗的转移性黑色素瘤患者中循环ANGPT 2的预测和预后价值。高治疗前血清ANGPT 2与CTLA-4和PD-1阻断治疗患者的总生存期降低相关。这些治疗也增加了许多患者在治疗开始后早期的血清ANGPT 2，而伊匹单抗加贝伐单抗治疗降低了血清浓度。ANGPT 2增加与缓解和/或总生存期降低相关。在一个患者亚组中，伊匹单抗增加了肿瘤血管ANGPT 2表达，伊匹单抗加贝伐单抗降低了肿瘤血管ANGPT 2表达，这分别与CD 68+和CD 163+巨噬细胞的肿瘤浸润增加和减少相关。在体外，贝伐珠单抗阻断VEGF诱导的肿瘤相关内皮细胞中的ANGPT 2表达，而ANGPT 2增加M2极化巨噬细胞上的PD-L1表达。治疗在接受临床益处的患者亚组中引起对ANGPT 2的持久和功能性抗体应答。我们的研究结果表明，血清ANGPT 2可被认为是免疫检查点治疗的预测和预后生物标志物，并可能通过增加肿瘤微环境中的促血管生成和免疫抑制活性而导致治疗抵抗。靶向ANGPT 2提供了一种合理的组合方法来提高免疫治疗的功效。
Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade-treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy.