Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma.
Indoleamine 2,3-dioxygenase provides adaptive resistance to immune checkpoint inhibitors in hepatocellular carcinoma.
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DOI：
10.1007/s00262-018-2190-4
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Greten TF
中科院分区：
文献类型：
--
作者：
Brown ZJ;Yu SJ;Heinrich B;Ma C;Fu Q;Sandhu M;Agdashian D;Zhang Q;Korangy F;Greten TF
肝细胞癌是全球第二大癌症相关死亡原因。用抗CTLA-4和抗PD-1抗体阻断免疫检查点在晚期肝癌患者的治疗中显示出良好的效果。根据目前的治疗标准，抗PD-1抗体nivolumab现在被批准用于患有进展性疾病的患者。然而，一部分接受免疫检查点抑制剂治疗的晚期肝癌患者对治疗没有反应。在这里，我们提供了通过上调吲哚胺2，3-双加氧酶(IDO)在肝细胞癌中对免疫检查点抑制剂产生适应性抵抗的证据。抗CTLA-4治疗可促进耐药肝细胞癌肿瘤中IDO1的诱导，但对免疫检查点阻断敏感的肿瘤则无此作用。使用皮下和肝脏原位模型，我们发现IDO抑制剂的添加增加了对IDO诱导率高的肝癌耐药肿瘤的治疗效果。此外，体内中和研究表明，免疫检查点阻断诱导的IDO依赖于干扰素-γ。抗PD-1治疗也观察到了类似的结果。这些结果提供了证据，证明IDO可能在肝癌患者对免疫检查点抑制剂的适应性抵抗中发挥作用。因此，联合抑制IDO和免疫检查点抑制剂可能会增加对过度表达IDO的肿瘤的治疗效果，应考虑用于肝细胞癌的临床评估。
Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death worldwide. Immune checkpoint blockade with anti-CTLA-4 and anti-PD-1 antibodies have shown promising results in the treatment of patients with advanced HCC. The anti-PD-1 antibody, nivolumab, is now approved for patients who have had progressive disease on the current standard of care. However, a subset of patients with advanced HCC treated with immune checkpoint inhibitors failed to respond to therapy. Here we provide evidence of adaptive resistance to immune checkpoint inhibitors through upregulation of indoleamine 2,3-dioxygenase (IDO) in HCC. Anti-CTLA-4 treatment promoted an induction of IDO1 in resistant HCC tumors but not in tumors sensitive to immune checkpoint blockade. Using both subcutaneous and hepatic orthotopic models, we found that the addition of an IDO inhibitor increases the efficacy of treatment in HCC resistant tumors with high IDO induction. Further, in vivo neutralizing studies demonstrated that the IDO induction by immune checkpoint blockade was dependent on IFN-γ. Similar findings were observed with anti-PD-1 therapy. These results provide evidence that IDO may play a role in adaptive resistance to immune checkpoint inhibitors in patients with HCC. Therefore, inhibiting IDO in combination with immune checkpoint inhibitors may add therapeutic benefit in tumors which overexpress IDO and should be considered for clinical evaluation in HCC.
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影响因子：
81.5
作者：
Llovet, Josep M.;Zucman-Rossi, Jessica;Gores, Gregory
通讯作者：
Gores, Gregory
影响因子：
8.8
作者：
Holmgaard RB;Zamarin D;Li Y;Gasmi B;Munn DH;Allison JP;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
16.6
作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
通讯作者：
Hammerman PS
DOI：
10.1177/1178646917735098
发表时间：
2017
期刊：
International journal of tryptophan research : IJTR
影响因子：
--
作者：
Jusof FF;Bakmiwewa SM;Weiser S;Too LK;Metz R;Prendergast GC;Fraser ST;Hunt NH;Ball HJ
通讯作者：
Ball HJ
影响因子：
10.9
作者：
Brown ZJ;Heinrich B;Steinberg SM;Yu SJ;Greten TF
通讯作者：
Greten TF