Distinct contribution of PD-L1 suppression by spatial expression of PD-L1 on tumor and non-tumor cells
Distinct contribution of PD-L1 suppression by spatial expression of PD-L1 on tumor and non-tumor cells
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PD-L1 在肿瘤和非肿瘤细胞上的空间表达对 PD-L1 抑制的独特贡献
DOI：
10.1038/s41423-018-0021-3
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发表时间：
2018-03
影响因子：
24.1
通讯作者：
Xuanming Yang
中科院分区：
文献类型：
--
作者：
Xiaoqing Zhang;Chen Cheng;Jiyan Hou;Xinyue Qi;Xin Wang;Ping Han;Xuanming Yang
程序性细胞死亡受体1(PD-1)及其配体PD-L1是重要的免疫检查点蛋白。尽管阻断PD-1/PD-L1的抗体已在部分癌症患者中显示出良好的临床疗效，但抗PD-1和抗PD-L1免疫治疗背后的详细细胞和分子机制尚不清楚。具体地说，PD-L1对肿瘤和非肿瘤细胞的免疫抑制作用的方式仍然存在争议。通过选择性地阻断肿瘤或非肿瘤细胞上的PD-L1，我们证明了这两种来源的PD-L1都抑制了抗肿瘤T细胞反应。阻断肿瘤细胞或非肿瘤细胞上的PD-L1可抑制肿瘤生长和增强免疫细胞的渗透，以及肿瘤特异性T细胞反应。此外，同时阻断肿瘤和非肿瘤来源的PD-L1可最大限度地提高抗肿瘤T细胞的反应，并显示出协同作用。此外，PD-L1对肿瘤和非肿瘤细胞免疫抑制的相对贡献依赖于PD-L1的表达水平。最后，我们发现F4/80受体参与了PD-L1阻滞剂的抗肿瘤作用。综上所述，我们的数据表明，肿瘤细胞和非肿瘤细胞上的PD-L1对T细胞的抑制都是至关重要的，这为PD-L1封闭抗体的优化和临床生物标志物策略的发展提供了新的方向。
Programmed cell death receptor 1 (PD-1) and its ligand, PD-L1, are important immune checkpoint proteins. Although antibodies that block PD-1/PD-L1 have shown promising clinical efficacy in a subset of cancer patients, the detailed cellular and molecular mechanisms behind anti-PD-1 and anti-PD-L1 immunotherapy are not well defined. Specifically, the way in which PD-L1 contributes to immune suppression on tumor and non-tumor cells remains controversial. By selectively blocking PD-L1 on either tumor or non-tumor cells, we demonstrated that PD-L1 from both sources suppressed the anti-tumor T-cell response. Blocking PD-L1 on either tumor cells or non-tumor cells inhibited tumor growth and enhanced immune cell infiltration, as well as the tumor-specific T-cell response. Further, simultaneously blocking tumor- and non-tumor-derived PD-L1 maximized anti-tumor T-cell responses and demonstrated synergy. In addition, the relative contribution of PD-L1 on tumor and non-tumor cells to immune suppression depended on the PD-L1 expression level. Lastly, we found that the F4/80 receptor was involved in the anti-tumor effect of PD-L1 blockade. Taken together, our data indicate that PD-L1 on both tumor and non-tumor cells is critical for T-cell inhibition, which provides new directions for the optimization of PD-L1-blocking antibodies and the development of clinical biomarker strategies.
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影响因子：
11.2
作者：
A. Johnsen;J. France;M. Sy;C. Harding
通讯作者：
A. Johnsen;J. France;M. Sy;C. Harding
DOI：
10.1084/jem.20160801
发表时间：
2017-04-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Juneja VR;McGuire KA;Manguso RT;LaFleur MW;Collins N;Haining WN;Freeman GJ;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
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
DOI：
10.1073/pnas.0712278105
发表时间：
2008-02-26
影响因子：
11.1
作者：
Lin, David Yin-Wei;Tanaka, Yoshimasa;Garboczi, David N.
通讯作者：
Garboczi, David N.