IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.
IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer.
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DOI：
10.1136/gutjnl-2016-311585
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发表时间：
2018-02
期刊：
影响因子：
24.5
通讯作者：
Lesinski GB
中科院分区：
文献类型：
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作者：
Mace TA;Shakya R;Pitarresi JR;Swanson B;McQuinn CW;Loftus S;Nordquist E;Cruz-Monserrate Z;Yu L;Young G;Zhong X;Zimmers TA;Ostrowski MC;Ludwig T;Bloomston M;Bekaii-Saab T;Lesinski GB
免疫检查点抑制剂在胰腺导管腺癌(PDAC)中的疗效有限，促使人们研究联合治疗。我们推测，阻断IL-6可以调节PDAC的免疫学特性，提高抗PD-L1检查点抑制剂治疗的疗效。采用纳米串分析和免疫组织化学方法分别检测原发患者星状细胞(PSC)转录水平和IL-6分泌水平。使用Panc02、MT5或KPC-Luc细胞系皮下或原位模型以及侵袭性的基因工程PDAC模型[KrasLSL-G12D、Trp53LSL-R270H、Pdx1.cre、Brca2F/F(KPC-BRCA2小鼠)]，用针对IL-6、PD-L1、CD4或CD8的抗体(Ab)进行体内疗效和机制研究。采用流式细胞仪或免疫组织化学检测免疫表型的全身性和局部性变化。患者来源的PSC(n=12)有明显的IL-6表达，免疫组织化学证实其定位于肿瘤间质。IL-6和PD-L1联合阻断对皮下移植瘤(P<；0.02)和Panc02肿瘤(P=0.046)小鼠均有疗效，并伴有瘤内效应T淋巴细胞(CD62L、−、CD44、−)的增加。在荷Panc02肿瘤的小鼠中，给予CD8耗竭而不是CD_4耗尽的单抗可取消IL-6和PD-L1联合阻断的效果(p=0.0016)。这种治疗组合还在携带KPC-Luc原位肿瘤的小鼠中诱导了显著的抗肿瘤活性，并限制了KPC-BRCA2小鼠的肿瘤进展(p<；0.001)。组织学分析显示多种模型肿瘤中T细胞浸润增加，α-SMA+细胞减少。最后，与同型对照相比，IL-6和PD-L1阻断可提高KPC-BRCA2小鼠的总体存活率(p=0.0012)。这些临床前研究结果表明，靶向抑制IL-6可增强PDAC中抗PD-L1的疗效。
Limited efficacy of immune checkpoint inhibitors in pancreatic ductal adenocarcinoma (PDAC) has prompted investigation into combination therapy. We hypothesized that IL-6 blockade would modulate immunologic features of PDAC and enhance the efficacy of anti-PD-L1 checkpoint inhibitor therapy. Transcription profiles and IL-6 secretion from primary patient stellate cells (PSC) were determined via nanostring analysis and immunohistochemistry, respectively. In vivo efficacy and mechanistic studies were conducted with antibodies (Ab) targeting IL-6, PD-L1, CD4, or CD8 in subcutaneous or orthotopic models using Panc02, MT5, or KPC-luc cell lines; and the aggressive, genetically engineered PDAC model [KrasLSL-G12D, Trp53LSL-R270H, Pdx1.cre, Brca2F/F (KPC-Brca2 mice)]. Systemic and local changes in immunophenotype were measured by flow cytometry or IHC as appropriate. Patient-derived PSC (n=12) demonstrated prominent IL-6 expression, which was localized to stroma of tumors as confirmed via immunohistochemistry. Combined IL-6 and PD-L1 blockade elicited efficacy in in mice bearing subcutaneous MT5 (p<0.02) and Panc02 tumors (p=0.046) which was accompanied by increased intratumoral effector T lymphocytes (CD62L− CD44−). Administration of CD8-depleting, but not CD4-depleting Ab abrogated the efficacy of combined IL-6 and PD-L1 blockade in mice bearing Panc02 tumors (p=0.0016). This treatment combination also elicited significant anti-tumor activity in mice bearing orthotopic KPC-luc tumors and limited tumor progression in KPC-Brca2 mice (p<0.001). Histologic analysis revealed increased T cell infiltration and reduced α-SMA+ cells in tumors from multiple models. Finally, IL-6 and PD-L1 blockade increased overall survival in KPC-Brca2 mice compared to isotype controls (p=0.0012). These pre-clinical results indicate that targeted inhibition of IL-6 may enhance the efficacy of anti-PD-L1 in PDAC.