Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma.
Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma.
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DOI：
10.1016/j.bbi.2017.01.022
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Wainwright DA
中科院分区：
文献类型：
--
作者：
Zhai L;Ladomersky E;Dostal CR;Lauing KL;Swoap K;Billingham LK;Gritsina G;Wu M;McCusker RH;Binder DC;Wainwright DA
胶质母细胞瘤(GBM)是成人最常见的恶性脑肿瘤，中位生存期14.6个月。GBM侵袭性的一个促成因素是瘤内表达免疫抑制酶吲哚胺2，3双加氧酶1(IDO1)。IDO1的酶活性与色氨酸转化为下游犬尿氨酸(Kyn)有关，此前已有假说认为这有助于抑制肿瘤免疫。利用同基因、免疫活性的颅内GL261细胞GBM模型，我们先前证明了肿瘤细胞IDO1抑制T细胞介导的小鼠脑瘤消退，而非肿瘤细胞IDO1。矛盾的是，我们还表明，免疫检查点阻断所介导的生存优势被非肿瘤细胞IDO1缺乏所废除。在这里，我们在过去观察的基础上，确认了肿瘤细胞IDO1在一种新的小鼠GBM模型中的适应不良作用。我们还证明，IDO1介导酶活性的主要贡献者是非肿瘤细胞，而不是小鼠GBM细胞。最后，我们展示了最有效的免疫检查点阻断介导的生存、非肿瘤细胞IDO1和基底膜内Kyn水平之间的新关联。这些数据首次表明，GBM细胞介导的免疫抑制不依赖IDO1酶，而免疫检查点阻断的生存益处需要非肿瘤细胞IDO1酶的活性。鉴于目前的临床抑制剂在靶向IDO1酶活性与酶非依赖性作用方面的作用机制不同，这项工作表明，选择合适的IDO1药物将使未来免疫检查点阻断方法的有效性最大化。
Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6 months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppresive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell-, but not non-tumor cell-IDO1, suppresses T cell-mediated brain tumor regression in mice. Paradoxically, we also showed that the survival advantage mediated by immune checkpoint blockade is abrogated by non-tumor cell IDO1-deficiency. Here, we have built on our past observations and confirm the maladaptive role of tumor cell IDO1 in a novel mouse GBM model. We also demonstrate that, non-tumor cells, rather than mouse GBM cells, are the dominant contributor to IDO1-mediated enzyme activity. Finally, we show the novel associations between maximally-effective immune-checkpoint blockade-mediated survival, non-tumor cell IDO1 and intra-GBM Kyn levels. These data suggest for the first time that, GBM cell-mediated immunosuppression is IDO1 enzyme independent, while the survival benefits of immune checkpoint blockade require non-tumor cell IDO1 enzyme activity. Given that current clinical inhibitors vary in their mechanism of action, in terms of targeting IDO1 enzyme activity versus enzyme-independent effects, this work suggests that choosing an appropriate IDO1 pharmacologic will maximize the effectiveness of future immune checkpoint blockade approaches.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
DOI：
10.1158/1078-0432.ccr-12-2130
发表时间：
2012-11-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Wainwright DA;Balyasnikova IV;Chang AL;Ahmed AU;Moon KS;Auffinger B;Tobias AL;Han Y;Lesniak MS
通讯作者：
Lesniak MS
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
DOI：
10.1158/1078-0432.ccr-14-0514
发表时间：
2014-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Wainwright DA;Chang AL;Dey M;Balyasnikova IV;Kim CK;Tobias A;Cheng Y;Kim JW;Qiao J;Zhang L;Han Y;Lesniak MS
通讯作者：
Lesniak MS
DOI：
10.1158/1078-0432.ccr-15-0420
发表时间：
2015-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Zhai L;Spranger S;Binder DC;Gritsina G;Lauing KL;Giles FJ;Wainwright DA
通讯作者：
Wainwright DA