Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade.
Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade.
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DOI：
10.1158/2159-8290.cd-19-1416
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发表时间：
2020-09
期刊：
影响因子：
28.2
通讯作者：
Haq R
中科院分区：
文献类型：
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作者：
Gstalder C;Liu D;Miao D;Lutterbach B;DeVine AL;Lin C;Shettigar M;Pancholi P;Buchbinder EI;Carter SL;Manos MP;Rojas-Rudilla V;Brennick R;Gjini E;Chen PH;Lako A;Rodig S;Yoon CH;Freeman GJ;Barbie DA;Hodi FS;Miles W;Van Allen EM;Haq R
导致PD-1阻断耐药的分子机制在很大程度上是未知的。在这里，我们描述了一个黑色素瘤患者的肿瘤活检，该患者对抗PD-1治疗表现出异质性反应。我们观察到耐药肿瘤在肿瘤抑制基因FBXW 7中表现出功能缺失突变，而同一患者的敏感肿瘤则没有。与免疫治疗应答中的功能作用一致，Fbxw 7在鼠肿瘤细胞系中的失活导致免疫活性动物对抗PD-1产生抗性。Fbxw 7的缺失与免疫微环境改变、dsRNA传感器Mda 5和Rig-I的肿瘤内在表达降低、I型干扰素和MHC-I表达的诱导减少相关。相比之下，Fbxw 7缺陷细胞中dsRNA感测的恢复足以使它们对抗PD-1敏感。因此，我们的研究结果为通常失活的肿瘤抑制因子FBXW 7在病毒传感和免疫治疗敏感性中建立了新的作用。
The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a melanoma patient who displayed heterogeneous responses to anti-PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, while a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti-PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the dsRNA sensors Mda5 and Rig-I, diminished induction of type I interferon and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient sensitize them to anti-PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy.