Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression
Phage display-identified PD-L1-binding peptides reinvigorate T-cell activity and inhibit tumor progression
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噬菌体显示鉴定的pd - l1结合肽重振t细胞活性并抑制肿瘤进展
DOI：
10.1016/j.biomaterials.2020.119984
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发表时间：
2020-07-01
期刊：
影响因子：
14
通讯作者：
Lee, Byungheon
中科院分区：
文献类型：
--
作者：
Gurung, Smriti;Khan, Fatima;Lee, Byungheon
阻断程序性细胞死亡配体-1（PD-L1）可恢复T细胞活性并增强抗肿瘤免疫力。筛选噬菌体展示肽文库中选择性结合PD-L1过表达细胞的肽，鉴定出两种似乎阻断PD-L1的肽CLQKTPKQC和CVRARTR（分别为PD-L1 Pep-1和PD-L1 Pep-2）。PD-L1 Pep-1和PD-L1 Pep-2优先与高PD-L1表达细胞结合，而非低PD-L1表达细胞;干扰素-γ（一种PD-L1表达诱导剂）可进一步增强结合。PD-L1 Pep-1和PD-L1 Pep-2的结合亲和力分别约为373和281 nM。PD-L1结合肽的细胞结合通过沉默PD-L1基因表达或与抗PD-L1抗体竞争而降低。PD-L1 Pep-1和PD-L1 Pep-2诱导PD-L1的内化和下调细胞表面水平。PD-L1结合肽恢复了细胞因子分泌和T细胞增殖，这些细胞通过与肿瘤细胞共培养或在PD-L1包被的平板上培养而受到抑制。腹膜内注射PD-L1 Pep-1和PD-L1 Pep-2可有效地归巢至肿瘤组织，抑制肿瘤生长，并增加小鼠中的CD 8 + /FoxP 3+比率。PD-L1结合肽与多柔比星或PD-L1靶向脂质体多柔比星的组合分别比单独的多柔比星和非靶向脂质体多柔比星更有效地抑制肿瘤生长和增加CD 8 + /FoxP 3+比率。这些结果表明PD-L1 Pep-1和PD-L1 Pep-2阻断PD-L1并重振T细胞活性，通过增强抗肿瘤免疫抑制肿瘤生长。
Blockade of programmed cell death ligand-1 (PD-L1) restores T-cell activity and enhances anti-tumor immunity. Screening a phage-displayed peptide library for peptides that selectively bind to PD-L1-overexpressing cells identified two peptides, CLQKTPKQC and CVRARTR (PD-L1Pep-1 and PD-L1Pep-2, respectively) that appeared to block PD-L1. PD-L1 Pep-1 and PD-L1 Pep-2 preferentially bound to high PD-L1 -expressing cells over low PD-L1-expressing cells; binding was further enhanced by interferon-gamma, an inducer of PD-L1 expression. Binding affinities of PD-L1 Pep-1 and PD-L1 Pep-2 were approximately 373 and 281 nM, respectively. Cellular binding of the PD-L1-binding peptides was reduced by silencing PD-Ll gene expression or competition with anti-PD-Ll antibody. PD-L1 Pep-1 and PD-L1 Pep-2 induced the internalization and downregulated cell surface levels of PD-Ll. The PD-L1-binding peptides restored cytokine secretion and T-cell proliferation to cells inhibited by co-culture with tumor cells or culture on PD-L1-coated plates. Intravenously injected PD-L1 Pep-1 and PD-L1 Pep-2 efficiently homed to tumor tissues, inhibited tumor growth, and increased CD8 + /FoxP3 + ratio in mice. The PD-Ll -binding peptides in combination with doxorubicin or PD-Ll -targeted liposomal doxorubicin inhibited tumor growth and increased CD8 + /FoxP3 + ratio more efficiently than doxorubicin alone and untargeted liposomal doxorubicin, respectively. These results suggest that PD-L1Pep-1 and PD-L1 Pep-2 block PD-Ll and reinvigorate T-cell activity, inhibiting tumor growth by enhancing anti-tumor immunity.