Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer.
Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer.
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DOI：
10.18632/oncotarget.7839
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发表时间：
2016-03-29
期刊：
影响因子：
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通讯作者：
Parangi S
中科院分区：
文献类型：
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作者：
Brauner E;Gunda V;Vanden Borre P;Zurakowski D;Kim YS;Dennett KV;Amin S;Freeman GJ;Parangi S
程序性细胞死亡-1及其配体的相互作用在癌症中被广泛研究。阻断这些分子的单抗已经取得了巨大的成功，但对它们在甲状腺癌中的作用知之甚少。我们从BRAF突变和MAPK通路活性方面研究了PD-L1在甲状腺癌中的作用，以及抗PD-L1抗体治疗单独或联合BRAF抑制剂(BRAFi)对肿瘤消退和瘤内免疫反应的影响。与BRAFWT细胞相比，BRAFV600E细胞的PD-L1在mRNA和蛋白水平的基线表达显著增加。MEK抑制剂处理后，所有细胞系的PD-L1表达均降低。BRAFi处理降低了BRAFV600E细胞中PD-L1的表达，但却相反地增加了其在BRAFWT细胞中的表达。BRAFV600E突变患者的PD-L1mRNA水平高于BRAFWT患者(p=0.015)。免疫活性小鼠(B6129SF1/J)接种同基因3747BRAFV600E/WT p53−/−小鼠肿瘤细胞，随机分为对照组、PLX4720、抗PD-L1抗体及其联合组。在该侵袭性甲状腺癌模型中，对照肿瘤体积在两周时达到782.3±174.6 mm~3。与PLX4720(439.3±188.4 mm~3，P=0.023)或PD-L1抗体(716.7±62.1，P<；0.001)相比，联合用药显著减少了肿瘤体积至147.3±60.8。免疫组织化学分析显示CD8+CTL浸润和细胞毒作用较强，CD8+/Treg比值良好。我们的结果表明，在ATC免疫活性模型中，抗PD-L1治疗增强了BRAFi对肿瘤消退的作用，并增强了抗肿瘤免疫反应。这种治疗组合的临床试验可能对ATC患者有益。
The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53−/− murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3±174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3±60.8, compared to PLX4720 (439.3±188.4 mm3, P=0.023) or PD-L1 antibody (716.7±62.1, P<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC.