Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.
Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy.
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DOI：
10.1016/j.cell.2016.08.069
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发表时间：
2016-10-06
期刊：
影响因子：
64.5
通讯作者：
Sharma, Padmanee
中科院分区：
文献类型：
--
作者：
Gao, Jianjun;Shi, Lewis Zhichang;Zhao, Hao;Chen, Jianfeng;Xiong, Liangwen;He, Qiuming;Chen, Tenghui;Roszik, Jason;Bernatchez, Chantale;Woodman, Scott E.;Chen, Pei-Ling;Hwu, Patrick;Allison, James P.;Futreal, Andrew;Wargo, Jennifer A.;Sharma, Padmanee
抗体阻断抑制CTLA-4途径已导致转移性黑色素瘤患者亚群的临床受益。抗CTLA-4增强T细胞反应，包括产生干扰素-γ，这是宿主免疫反应的关键细胞因子。然而，肿瘤细胞中干扰素-γ信号在抗CTLA-4治疗中的作用尚不清楚。在这里，我们证明了被确认为对抗CTLA-4(Ipilimumab)无应答的患者存在干扰素-γ途径基因的基因组缺陷。此外，携带干扰素-γ受体1(IFNGR1)敲除的黑色素瘤小鼠在抗CTLA-4治疗时已削弱了肿瘤排斥反应。这些数据表明，干扰素-γ信号通路的缺失与抗CTLA-4治疗的原发耐药性有关。我们的发现证明了肿瘤基因组数据的重要性，特别是干扰素-γ相关基因，作为选择接受免疫检查点治疗的患者的预后信息。在人类和实验模型中，干扰素途径基因中的基因组缺陷降低了使用抗CTLA-4进行免疫检查点阻断治疗黑色素瘤的反应机会。
Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy. Genomic defects in the interferon pathway genes reduce the chance of response to immune checkpoint blockade therapy with anti-CTLA-4 for melanoma in humans and experimental models.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
11.2
作者：
Peng W;Liu C;Xu C;Lou Y;Chen J;Yang Y;Yagita H;Overwijk WW;Lizée G;Radvanyi L;Hwu P
通讯作者：
Hwu P
影响因子：
11.2
作者：
Dunn, GP;Sheehan, KCF;Schreiber, RD
通讯作者：
Schreiber, RD
DOI：
10.1073/pnas.0806075105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Liakou, Chrysoula I.;Kamat, Ashish;Sharma, Padmanee
通讯作者：
Sharma, Padmanee
影响因子：
24.5
作者：
Detjen, KM;Farwig, K;Rosewicz, S
通讯作者：
Rosewicz, S