CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models
CD19-targeting fusion protein combined with PD1 antibody enhances anti-tumor immunity in mouse models
复制标题
CD19靶向融合蛋白联合PD1抗体增强小鼠模型的抗肿瘤免疫力
DOI：
10.1080/2162402x.2020.1747688
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发表时间：
2020-01-01
期刊：
影响因子：
7.2
通讯作者：
Ji, Yanhong
中科院分区：
文献类型：
--
作者：
Lv, Zhuangwei;Zhang, Ping;Ji, Yanhong
摘要：在我们之前的研究中，使用 B 细胞疫苗 (scFv-Her2)，通过抗 CD19 单链可变片段 (scFv) 将肿瘤相关抗原 Her2（人表皮生长因子受体 2）靶向 B 细胞，结果显示可以增强肿瘤特异性免疫，从而增强预防和治疗环境中的肿瘤控制。然而，融合蛋白对已形成的肿瘤表现出有限的活性，并且在 scFv-Her2 治疗后经常发生局部复发，表明 scFv-Her2 诱导的反应不足以维持抗肿瘤免疫。在这项研究中，通过CD19分子（scFv-Her2D4）将Her2胞外区的IV区（D4）靶向B细胞，发现可以增强肿瘤组织中产生IFN-γ的CD8+ T细胞浸润，并减少肿瘤浸润的骨髓源性抑制细胞（MDSC）的数量。然而，scFv-Her2D4 处理后，肿瘤微环境中的负共刺激分子，如 T 细胞上的程序性细胞死亡蛋白 1 (PD-1)、CD160 和 LAG-3 以及肿瘤细胞上的程序性死亡蛋白配体 1 (PD-L1) 上调。此外，抗PD1给药增强了scFv-Her2D4和抗肿瘤免疫的功效，这一点可以通过逆转肿瘤浸润CD8+T细胞耗竭以及MDSC和Treg细胞的减少来证明，从而抑制T细胞并改变肿瘤免疫微环境。此外，将其与抗 PD1 抗体相结合可促进肿瘤的完全排斥。我们的数据提供了肿瘤疫苗、T细胞和PD-L1/PD-1轴之间密切相互作用的证据，并为合理设计免疫调节剂和肿瘤疫苗疗法的联合治疗奠定了基础。
ABSTRACT In our previous studies, using a B cell vaccine (scFv-Her2), the targeting of tumor-associated antigen Her2 (human epidermal growth factor receptor-2) to B cells via the anti-CD19 single chain variable fragment (scFv) was shown to augment tumor-specific immunity, which enhanced tumor control in the prophylactic and therapeutic setting. However, the fusion protein displayed limited activity against established tumors, and local relapses often occurred following scFv-Her2 treatment, indicating that scFv-Her2-induced responses are inadequate to maintain anti-tumor immunity. In this study, targeting the IV region (D4) of the extracellular region of Her2 to B cells via CD19 molecules (scFv-Her2D4) was found to enhance IFN-γ-producing-CD8+ T cell infiltration in tumor tissues and reduced the number of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). However, negative co-stimulatory molecules such as programmed cell death protein-1 (PD-1), CD160, and LAG-3 on T cells and programmed death protein ligand-1 (PD-L1) on tumor cells were upregulated in the tumor microenvironment after scFv-Her2D4 treatment. Further, anti-PD1 administration enhanced the efficacy of scFv-Her2D4 and anti-tumor immunity, as evidenced by the reversal of tumor-infiltrating CD8+ T cell exhaustion and the reduction of MDSCs and Treg cells, which suppress T cells and alter the tumor immune microenvironment. Moreover, combining this with anti-PD1 antibodies promoted complete tumor rejection. Our data provide evidence of a close interaction among tumor vaccines, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and tumor vaccine therapy.