Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion.
Trastuzumab upregulates PD-L1 as a potential mechanism of trastuzumab resistance through engagement of immune effector cells and stimulation of IFNγ secretion.
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DOI：
10.1016/j.canlet.2018.05.009
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发表时间：
2018-08-28
期刊：
影响因子：
9.7
通讯作者：
Fan Z
中科院分区：
文献类型：
--
作者：
Chaganty BKR;Qiu S;Gest A;Lu Y;Ivan C;Calin GA;Weiner LM;Fan Z
在这里，我们报告了在对人HER 2免疫耐受的转基因小鼠模型中，用抗人HER 2抗体曲妥珠单抗治疗转导过表达人表皮生长因子受体-2（HER 2）的同基因小鼠肿瘤上调了程序性死亡配体1（PD-L1）的水平，PD-L1是T细胞应答的重要负调节因子。我们进一步发现，单独使用曲妥珠单抗对HER 2过表达人乳腺癌细胞的单一培养物中的PD-L1表达水平没有可检测的影响，但当与人外周血单核细胞共培养时，在同一组HER 2过表达乳腺癌细胞中上调PD-L1，并且PD-L1的上调可被IFNγ中和抗体阻断。通过HER 2表达敲低或激酶抑制抑制HER 2内在信号传导对下调PD-L1水平具有可变和细胞环境特异性影响。对癌症基因组图谱数据库的分析显示，HER 2和PD-L1在信使RNA水平上没有直接相关性。曲妥珠单抗通过免疫效应细胞介导的PD-L1上调可能是曲妥珠单抗耐药的潜在机制。我们的数据证明了进一步研究在基于曲妥珠单抗的治疗中添加抗PD-1或抗PD-L1治疗的价值。
Here, we report that treatment of syngeneic mouse tumors transduced to overexpress human epidermal growth factor receptor-2 (HER2) with the anti-human HER2 antibody trastuzumab upregulated the level of programmed death-ligand 1 (PD-L1), an important negative regulator of T-cell response, in a transgenic mouse model immune-tolerant to human HER2. We further found that trastuzumab alone had no detectable effect on the level of PD-L1 expression in monocultures of HER2-overexpressing human breast cancer cells but upregulated PD-L1 in the same panel of HER2-overexpressing breast cancer cells when they were co-cultured with human peripheral blood mononuclear cells, and the upregulation of PD-L1 could be blocked by an IFNγ-neutralizing antibody. Inhibition of HER2 intrinsic signaling via HER2 expression knockdown or kinase inhibition had variable and cell-context-specific effects on downregulating the PD-L1 level. Analysis of The Cancer Genome Atlas database showed no direct correlation between HER2 and PD-L1 at the messenger RNA level. Trastuzumab-mediated upregulation of PD-L1 through engagement of immune effector cells may function as a potential mechanism of trastuzumab resistance. Our data justify further investigation of the value of adding anti-PD-1 or anti-PD-L1 therapy to trastuzumab-based treatment.
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影响因子：
8.8
作者：
Ladoire, S.;Arnould, L.;Mignot, G.;Apetoh, L.;Rebe, C.;Martin, F.;Fumoleau, P.;Coudert, B.;Ghiringhelli, F.
通讯作者：
Ghiringhelli, F.
DOI：
10.1158/1078-0432.ccr-15-1125
发表时间：
2016-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Loi S;Dushyanthen S;Beavis PA;Salgado R;Denkert C;Savas P;Combs S;Rimm DL;Giltnane JM;Estrada MV;Sánchez V;Sanders ME;Cook RS;Pilkinton MA;Mallal SA;Wang K;Miller VA;Stephens PJ;Yelensky R;Doimi FD;Gómez H;Ryzhov SV;Darcy PK;Arteaga CL;Balko JM
通讯作者：
Balko JM
影响因子：
3.5
作者：
Lee, SJ;Jang, BC;Choi, IH
通讯作者：
Choi, IH
影响因子：
7.4
作者：
Beano, Alessandra;Signorino, Elena;Matera, Lina
通讯作者：
Matera, Lina
影响因子：
64.8
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
通讯作者：
Hodi FS