PD-L1(P146R) is prognostic and a negative predictor of response to immunotherapy in gastric cancer.
PD-L1(P146R) is prognostic and a negative predictor of response to immunotherapy in gastric cancer.
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PD-L1P146R 是胃癌免疫治疗反应的预后因子和阴性预测因子。
DOI：
10.1016/j.ymthe.2021.09.013
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发表时间：
2022-02-02
期刊：
影响因子：
--
通讯作者：
Xu CX
中科院分区：
文献类型：
--
作者：
Li Q;Zhou ZW;Lu J;Luo H;Wang SN;Peng Y;Deng MS;Song GB;Wang JM;Wei X;Wang D;Westover KD;Xu CX
癌细胞通过程序性细胞死亡1/程序性细胞死亡配体1（PD-1/PD-L1）相互作用逃避免疫检测，这些相互作用使T细胞活化。PD-1/PD-L1阻断剂已成为抗癌药物中的重要疗法。然而，一些患者尽管表达PD-L1，但不能从PD-1/PD-L1阻断中获益。在这里，我们筛选了101名胃癌（GC）患者和141名健康对照受试者，并报告了一个这样的GC患者亚群，其PD-L1中的rs 17718883多态性导致无义P146 R突变。我们在44%的健康对照受试者中检测到rs 17718883，rs 17718883与GC患者的低易感性和较好的预后相关。结构分析表明，突变减弱了PD-1：PD-L1相互作用。这得到了T细胞共培养实验的支持，GC细胞显示P146 R取代导致T细胞分泌干扰素（IFN）-γ，并使T细胞能够抑制GC细胞生长。在体内获得了与动物胃肿瘤模型相似的结果。PD-1单克隆抗体处理在体外或体内均未增强T细胞对表达PD-L1 P146 R的GC细胞的抑制作用。这项研究表明，rs 17718883是常见的，可用作排除PD-1/PD-L1阻断治疗的生物标志物。PD-L1突变P146 R是胃癌患者PD-1/PD-L1阻断治疗应答的预后和阴性预测因子，建立了PD-1/PD-L1阻断治疗中胃癌患者选择的潜在排除标准。
Cancer cells evade immune detection via programmed cell death 1/programmed cell death-ligand 1 (PD-1/PD-L1) interactions that inactivate T cells. PD-1/PD-L1 blockade has become an important therapy in the anti-cancer armamentarium. However, some patients do not benefit from PD-1/PD-L1 blockade despite expressing PD-L1. Here, we screened 101 gastric cancer (GC) patients at diagnosis and 141 healthy control subjects and reported one such subpopulation of GC patients with rs17718883 polymorphism in PD-L1, resulting in a nonsense P146R mutation. We detected rs17718883 in 44% of healthy control subjects, and rs17718883 was associated with a low susceptibility to GC and better prognosis in GC patients. Structural analysis suggests that the mutation weakens the PD-1:PD-L1 interaction. This was supported by co-culture experiments of T cells, with GC cells showing that the P146R substitution results in interferon (IFN)-γ secretion by T cells and enables T cells to suppress GC cell growth. Similar results with animal gastric tumor models were obtained in vivo. PD-1 monoclonal antibody treatment did not enhance the inhibitory effect of T cells on GC cells expressing PD-L1P146Rin vitro or in vivo. This study suggests that rs17718883 is common and may be used as a biomarker for exclusion from PD-1/PD-L1 blockade therapy. PD-L1 mutation P146R is prognostic and a negative predictor of response to PD-1/PD-L1 blockade therapy in gastric cancer, establishing a potential exclusion criterion for gastric cancer patient selection in PD-1/PD-L1 blockade therapy.
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影响因子：
28.5
作者：
Tessoulin, Benoit;Moreau-Aubry, Agnes;Pellat-Deceunynck, Catherine
通讯作者：
Pellat-Deceunynck, Catherine
影响因子：
3.5
作者：
Lee, Shin Yup;Jung, Deuk Kju;Park, Jae Yong
通讯作者：
Park, Jae Yong
影响因子：
3.5
作者：
Xie, Qigui;Chen, Zhanlei;Yang, Zhuying
通讯作者：
Yang, Zhuying
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA