Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade
Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade
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DOI：
10.1038/s41416-020-0757-2
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发表时间：
2020-02-18
影响因子：
8.8
通讯作者：
Kaisho, Tsuneyasu
中科院分区：
文献类型：
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作者：
Mizumoto, Yuki;Hemmi, Hiroaki;Kaisho, Tsuneyasu
背景癌症肽疫苗对癌症仅显示边缘效应。免疫检查点抑制剂（ICI）在某些类型的癌症中显示出显著的疗效，但反应率仍然有限。在这项研究中，我们的目标是通过将Ag肽选择性地靶向树突状细胞（DC）亚群，表达XCR 1的DC（XCR 1（+）DC），具有高支持CD 8（+）T细胞应答的能力，来改善癌症肽疫苗接种。方法我们制备了一种由MHC Ⅰ类分子呈递的抗原肽和XCR 1配体XCL 1组成的融合蛋白，并检测了其对小鼠抗肿瘤免疫的影响。结果融合蛋白以XCR 1依赖的方式被递送至XCR 1（+）DC。用融合蛋白加上免疫佐剂聚肌苷酸：聚胞苷酸（poly（I：C））免疫，比Ag肽加上poly（I：C）或Ag蛋白加上poly（I：C）更有效地通过XCR 1诱导Ag特异性CD 8（+）T细胞应答。在预防性和治疗性肿瘤模型中，融合蛋白加poly（I：C）有效地抑制肿瘤生长。此外，融合蛋白加上poly（I：C）与抗PD-1 Ab协同显示对肿瘤生长的抑制作用。结论肿瘤抗原靶向XCR 1（+）DCs作为免疫检查点阻断联合抗肿瘤治疗是一种很有前景的方法。
Background Cancer peptide vaccines show only marginal effects against cancers. Immune checkpoint inhibitors (ICIs) show significant curative effects in certain types of cancers, but the response rate is still limited. In this study, we aim to improve cancer peptide vaccination by targeting Ag peptides selectively to a dendritic cell (DC) subset, XCR1-expressing DCs (XCR1(+) DCs), with high ability to support CD8(+) T-cell responses. Methods We have generated a fusion protein, consisting of an Ag peptide presented with MHC class I, and an XCR1 ligand, XCL1, and examined its effects on antitumour immunity in mice. Results The fusion protein was delivered to XCR1(+) DCs in an XCR1-dependent manner. Immunisation with the fusion protein plus an immune adjuvant, polyinosinic:polycytidylic acids (poly(I:C)), more potently induced Ag-specific CD8(+) T-cell responses through XCR1 than the Ag peptide plus poly(I:C) or the Ag protein plus poly(I:C). The fusion protein plus poly(I:C) inhibited the tumour growth efficiently in the prophylactic and therapeutic tumour models. Furthermore, the fusion protein plus poly(I:C) showed suppressive effects on tumour growth in synergy with anti-PD-1 Ab. Conclusions Cancer Ag targeting to XCR1(+) DCs should be a promising procedure as a combination anticancer therapy with immune checkpoint blockade.