Blockage of immune checkpoint molecules increases T-cell priming potential of dendritic cell vaccine
Blockage of immune checkpoint molecules increases T-cell priming potential of dendritic cell vaccine
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DOI：
10.1111/imm.13126
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发表时间：
2019-10-24
期刊：
影响因子：
6.4
通讯作者：
Jadidi-Niaragh, Farhad
中科院分区：
文献类型：
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作者：
Hassannia, Hadi;Ghasemi Chaleshtari, Mitra;Jadidi-Niaragh, Farhad
以树突状细胞(DC)为基础的肿瘤免疫治疗是最重要的抗癌免疫疗法之一，在不同的癌症类型中具有不同的疗效。众所周知，肿瘤微环境在DC疫苗等多种免疫疗法的疗效中起着关键作用。相应地，DC上的程序性死亡配体1(PD-L1)的表达与T细胞上的PD-1相互作用，导致DC向T细胞递送肿瘤抗原后抗肿瘤反应的抑制。因此，我们假设DC中PD-L1的下调与PD-1在T细胞上的沉默相关，可能导致DC增强T细胞的启动，从而具有有效的抗肿瘤T细胞反应。在本研究中，我们通过小干扰RNA(SiRNA)负载的壳聚糖硫酸葡聚糖纳米粒(NPs)沉默DC中PD-L1的表达和T细胞中程序性细胞死亡蛋白1(PD-1)的表达，并对DC体外识别肿瘤抗原后的表型、功能特征和T细胞功能进行了研究。结果表明，合成的纳米粒子具有良好的物理化学特性(大小为77个中心点5 nm，Zeta电位为14个中心点3)，与有效的细胞摄取和靶基因沉默有关。此外，PD-L1沉默与DC的刺激特性有关。另一方面，PD-L1阴性的树突状细胞向PD-1沉默的T细胞递送肿瘤抗原导致了强大的T细胞反应的诱导。我们的发现表明，PD-L1沉默的DC可以被认为是与PD-1-siRNA负载的NPs相结合的一种有效的免疫治疗方法；然而，还需要在动物模型中进行进一步的体内研究。
Dendritic cell (DC) -based cancer immunotherapy is one of the most important anti-cancer immunotherapies, and has been associated with variable efficiencies in different cancer types. It is well-known that tumor microenvironment plays a key role in the efficacy of various immunotherapies such as DC vaccine. Accordingly, the expression of programmed death ligand 1 (PD-L1) on DCs, which interacts with PD-1 on T cells, leads to inhibition of anti-tumor responses following presentation of tumor antigens by DCs to T cells. Therefore, we hypothesized that down-regulation of PD-L1 in DCs in association with silencing of PD-1 on T cells may lead to the enhancement of T-cell priming by DCs to have efficient anti-tumor T-cell responses. In this study, we silenced the expression of PD-L1 in DCs and programmed cell death protein 1 (PD-1) in T cells by small interfering RNA (siRNA) -loaded chitosan-dextran sulfate nanoparticles (NPs) and evaluated the DC phenotypic and functional characteristics and T-cell functions following tumor antigen recognition on DCs, ex vivo. Our results showed that synthesized NPs had good physicochemical characteristics (size 77 center dot 5 nm and zeta potential of 14 center dot 3) that were associated with efficient cellular uptake and target gene silencing. Moreover, PD-L1 silencing was associated with stimulatory characteristics of DCs. On the other hand, presentation of tumor antigens by PD-L1-negative DCs to PD-1-silenced T cells led to induction of potent T-cell responses. Our findings imply that PD-L1-silenced DCs can be considered as a potent immunotherapeutic approach in combination with PD-1-siRNA loaded NPs, however; further in vivo investigation is required in animal models.