TIGIT and PD-1 Immune Checkpoint Pathways Are Associated With Patient Outcome and Anti-Tumor Immunity in Glioblastoma.
TIGIT and PD-1 Immune Checkpoint Pathways Are Associated With Patient Outcome and Anti-Tumor Immunity in Glioblastoma.
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DOI：
10.3389/fimmu.2021.637146
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发表时间：
2021
影响因子：
7.3
通讯作者：
Kohanbash G
中科院分区：
文献类型：
--
作者：
Raphael I;Kumar R;McCarl LH;Shoger K;Wang L;Sandlesh P;Sneiderman CT;Allen J;Zhai S;Campagna ML;Foster A;Bruno TC;Agnihotri S;Hu B;Castro BA;Lieberman FS;Broniscer A;Diaz AA;Amankulor NM;Rajasundaram D;Pollack IF;Kohanbash G
胶质母细胞瘤(GBM)是一种高死亡率的侵袭性脑瘤。免疫检查点(IC)分子表达在肿瘤浸润性淋巴细胞(TIL)上，与肿瘤细胞表达的免疫检查点(IC)配体结合后促进T细胞的耗竭。通过免疫治疗干扰IC通路，促进了抗肿瘤免疫的重新激活，并导致了几种恶性肿瘤的成功。然而，IC抑制剂在GBM患者中取得的成功有限，这表明其他检查点分子可能参与抑制TIL反应。已经描述了许多IC通路，目前正在进行多个临床试验中的抑制剂测试。确定最有希望的检查点通路可能有助于指导未来的GBM试验。在这里，我们分析了癌症基因组图谱(TCGA)转录数据库，并确定PD1和TIGIT是GBM免疫治疗的首选靶点。此外，在小鼠GBM模型中，与单独使用任何一种药物相比，双重阻断PD1和TIGIT可提高存活率，增加CD8+TIL的积聚和功能。此外，在我们的小鼠胶质瘤中，我们证明这种联合免疫疗法影响粒/多形核(PMN)髓系衍生抑制细胞(MDSCs)，但不影响单核细胞(Mo)MDSCs。重要的是，我们发现抑制性髓系细胞在人GBM组织中表达PD1、PD-L1和TIGIT-配体，并证明被免疫抑制髓系细胞抑制的抗原特异性T细胞增殖可以通过TIGIT/PD1阻断而恢复。我们的数据为了解αPD1/α免疫治疗的机制提供了新的见解。
Glioblastoma (GBM) remains an aggressive brain tumor with a high rate of mortality. Immune checkpoint (IC) molecules are expressed on tumor infiltrating lymphocytes (TILs) and promote T cell exhaustion upon binding to IC ligands expressed by the tumor cells. Interfering with IC pathways with immunotherapy has promoted reactivation of anti-tumor immunity and led to success in several malignancies. However, IC inhibitors have achieved limited success in GBM patients, suggesting that other checkpoint molecules may be involved with suppressing TIL responses. Numerous IC pathways have been described, with current testing of inhibitors underway in multiple clinical trials. Identification of the most promising checkpoint pathways may be useful to guide the future trials for GBM. Here, we analyzed the The Cancer Genome Atlas (TCGA) transcriptomic database and identified PD1 and TIGIT as top putative targets for GBM immunotherapy. Additionally, dual blockade of PD1 and TIGIT improved survival and augmented CD8+ TIL accumulation and functions in a murine GBM model compared with either single agent alone. Furthermore, we demonstrated that this combination immunotherapy affected granulocytic/polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) but not monocytic (Mo) MDSCs in in our murine gliomas. Importantly, we showed that suppressive myeloid cells express PD1, PD-L1, and TIGIT-ligands in human GBM tissue, and demonstrated that antigen specific T cell proliferation that is inhibited by immunosuppressive myeloid cells can be restored by TIGIT/PD1 blockade. Our data provide new insights into mechanisms of GBM αPD1/αTIGIT immunotherapy.
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影响因子：
--
作者：
Dong Y;Sun Q;Zhang X
通讯作者：
Zhang X
影响因子：
4.3
作者：
Chase Huizar C;Raphael I;Forsthuber TG
通讯作者：
Forsthuber TG
倒退时间：靶向肿瘤浸润髓样细胞以恢复癌症的进展。
影响因子：
7.3
作者：
Awad RM;De Vlaeminck Y;Maebe J;Goyvaerts C;Breckpot K
通讯作者：
Breckpot K
影响因子：
7.2
作者：
Hung AL;Maxwell R;Theodros D;Belcaid Z;Mathios D;Luksik AS;Kim E;Wu A;Xia Y;Garzon-Muvdi T;Jackson C;Ye X;Tyler B;Selby M;Korman A;Barnhart B;Park SM;Youn JI;Chowdhury T;Park CK;Brem H;Pardoll DM;Lim M
通讯作者：
Lim M
DOI：
10.1158/1078-0432.ccr-17-2769
发表时间：
2018-11-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Buerki RA;Chheda ZS;Okada H
通讯作者：
Okada H