Tseng Ssu-Hsueh, Cheng Max A, Farmer Emily, Ferrall Louise, Kung Yu Jui, Lam Brandon, Lim Ling, Wu T-C, Hung Chien-Fu
Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Stanford Medicine, Stanford University School of Medicine, Stanford, California, USA.
J Immunother Cancer. 2022 Apr;10(4). doi: 10.1136/jitc-2021-004342.
Type I interferons (IFN) promote dendritic cells maturation and subsequently enhance generation of antigen-specific CD8 +T cell for the control of tumor. Using type I interferons as an adjuvant to vaccination could prove to be a potent strategy. However, type I interferons have a short half-life. Albumin linked to a protein will prolong the half-life of the linked protein.
In this study, we explored the fusion of albumin to IFNβ (Alb-IFNβ) for its functional activity both in vitro and in vivo. We determined the half-life of Alb-IFNβ following treatment in the serum, tumor, and tumor draining lymph nodes in both wild type and FcRn knockout mice. We characterized the ability of Alb-IFNβ to enhance antigen-specific CD8+ T cells using ovalbumin (OVA) or human papillomavirus (HPV) E7 long peptides. Next, we evaluated the therapeutic antitumor effect of coadministration of AlbIFNβ with antigenic peptides against HPVE7 expressing tumor and the treatment's ability to generate HPVE7 antigen specific CD8+ T cells. The contribution of the antitumor effect by lymphocytes was also examined by an antibody depletion experiment. The ability of Alb-IFNβ to serve as an adjuvant was tested using clinical grade therapeutic protein-based HPV vaccine, TACIN.
Alb-IFNβ retains biological function and does not alter the biological activity of IFNβ. In addition, Alb-IFNβ extends half-life of IFNβ in serum, lymph nodes and tumor. The coadministration of Alb-IFNβ with OVA or HPVE7 antigenic peptides enhances antigen-specific CD8 +T cell immunity, and in a TC-1 tumor model results in a significant therapeutic antitumor effect. We found that CD8 +T cells and dendritic cells, but not CD4 +T cells, are important for the observed antitumor therapeutic effect mediated by Alb-IFNβ. Finally, Alb-IFNβ served as a potent adjuvant for TA-CIN for the treatment of HPV antigen expressing tumors.
Overall, Alb-IFNβ serves as a potent adjuvant for enhancement of strong antigen-specific CD8 +T cell antitumor immunity, reduction of tumor burden, and increase in overall survival. Alb-IFNβ potentially can serve as an innovative adjuvant for the development of vaccines for the control of infectious disease and cancer.
I型干扰素（IFN）可促进树突状细胞成熟，进而增强抗原特异性CD8 + T细胞的生成以控制肿瘤。使用I型干扰素作为疫苗佐剂可能是一种有效的策略。然而，I型干扰素半衰期较短。与蛋白质连接的白蛋白可延长连接蛋白的半衰期。
在本研究中，我们探究了白蛋白与IFNβ融合蛋白（Alb-IFNβ）在体外和体内的功能活性。我们测定了野生型和FcRn基因敲除小鼠血清、肿瘤及肿瘤引流淋巴结中Alb-IFNβ处理后的半衰期。我们使用卵清蛋白（OVA）或人乳头瘤病毒（HPV）E7长肽来表征Alb-IFNβ增强抗原特异性CD8 + T细胞的能力。接下来，我们评估了Alb-IFNβ与抗原肽联合给药对表达HPV E7的肿瘤的治疗抗肿瘤效果以及该治疗产生HPV E7抗原特异性CD8 + T细胞的能力。还通过抗体清除实验检测了淋巴细胞对抗肿瘤效果的贡献。使用临床级基于治疗性蛋白的HPV疫苗TACIN测试了Alb-IFNβ作为佐剂的能力。
Alb-IFNβ保留生物学功能且不改变IFNβ的生物活性。此外，Alb-IFNβ延长了IFNβ在血清、淋巴结和肿瘤中的半衰期。Alb-IFNβ与OVA或HPV E7抗原肽联合给药可增强抗原特异性CD8 + T细胞免疫，在TC-1肿瘤模型中产生显著的治疗抗肿瘤效果。我们发现CD8 + T细胞和树突状细胞而非CD4 + T细胞对Alb-IFNβ介导的观察到的抗肿瘤治疗效果很重要。最后，Alb-IFNβ作为TA-CIN治疗表达HPV抗原肿瘤的有效佐剂。
总体而言，Alb-IFNβ作为一种有效的佐剂，可增强强大的抗原特异性CD8 + T细胞抗肿瘤免疫，减轻肿瘤负担并提高总生存率。Alb-IFNβ有可能作为一种创新佐剂用于开发控制传染病和癌症的疫苗。
