Tian Yaomei, Hu Qiuyue, Zhang Rui, Zhou Bailing, Xie Daoyuan, Wang Yuanda, Zhang Xueyan, Yang Li
Department of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.
College of Bioengineering, Sichuan University of Science & Engineering, Zigong, Sichuan, PR China.
NPJ Vaccines. 2021 May 20;6(1):75. doi: 10.1038/s41541-021-00334-3.
The development of adjuvants has been an empirical process. Efforts to develop a new design and evaluation system for novel adjuvants are not only desirable but also necessary. Moreover, composite adjuvants that contain two or more types of adjuvants to synergistically enhance the immune response are important for adjuvant and vaccine design. Innate defense regulator peptides (IDRs) are promising adjuvants for clinical immunotherapy because they exhibit multifaceted immunomodulatory capabilities. However, the rational design and discovery of IDRs that have improved immunomodulatory activities have been hampered by the lack of screening techniques and the great challenges in the identification of their interaction partners. Here, we describe a screening and evaluation system for IDR design. On the basis of in vitro screening, the optimized IDR DP7 recruited neutrophils, monocytes and macrophages to the site of infection. The adjuvant, comprising the DP7 and CpG oligonucleotide (CpG), induced chemokine/cytokine expression, enhanced the antigen uptake by dendritic cells and upregulated surface marker expression in dendritic cells. Vaccination with the NY-ESO-1 or OVA antigens combined with the adjuvant alum/CpG/DP7 strongly suppressed tumor growth in mice which was due to the improvement of antigen-specific humoral and cellular immunity. Regarding the mechanism of action, GPR35 may be the potential interaction partner of DP7. Our study revealed the potential application of the screening and evaluation system as a strategy for rationally designing effective IDRs or composite adjuvants and identifying their mechanism of action.
佐剂的研发一直是一个经验性的过程。开发针对新型佐剂的新设计和评估系统不仅是可取的，而且是必要的。此外，包含两种或更多种佐剂以协同增强免疫反应的复合佐剂对于佐剂和疫苗设计很重要。固有防御调节肽（IDR）是临床免疫治疗中有前景的佐剂，因为它们具有多方面的免疫调节能力。然而，由于缺乏筛选技术以及在鉴定其相互作用伙伴方面面临巨大挑战，具有改善免疫调节活性的IDR的合理设计和发现受到了阻碍。在此，我们描述了一种用于IDR设计的筛选和评估系统。基于体外筛选，优化后的IDR DP7将中性粒细胞、单核细胞和巨噬细胞募集到感染部位。由DP7和CpG寡核苷酸（CpG）组成的佐剂可诱导趋化因子/细胞因子表达，增强树突状细胞对抗原的摄取，并上调树突状细胞表面标志物的表达。用NY-ESO-1或OVA抗原与佐剂明矾/CpG/DP7联合接种可强烈抑制小鼠肿瘤生长，这是由于抗原特异性体液免疫和细胞免疫得到改善。关于作用机制，GPR35可能是DP7的潜在相互作用伙伴。我们的研究揭示了筛选和评估系统作为合理设计有效IDR或复合佐剂并确定其作用机制的策略的潜在应用。
