Wylie Ben, Ong Ferrer, Belhoul-Fakir Hanane, Priebatsch Kristin, Bogdawa Heique, Stirnweiss Anja, Watt Paul, Cunningham Paula, Stone Shane R, Waithman Jason
Telethon Kids Institute, The University of Western Australia, Nedlands, WA 6009, Australia.
PYC Therapeutics, Harry Perkins Institute, QEII Medical Centre, Nedlands, WA 6009, Australia.
Cancers (Basel). 2021 Dec 8;13(24):6189. doi: 10.3390/cancers13246189.
Cross-presenting dendritic cells (DC) offer an attractive target for vaccination due to their unique ability to process exogenous antigens for presentation on MHC class I molecules. Recent reports have established that these DC express unique surface receptors and play a critical role in the initiation of anti-tumor immunity, opening the way for the development of vaccination strategies specifically targeting these cells. This study investigated whether targeting cross-presenting DC by two complementary mechanisms could improve vaccine effectiveness, in both a viral setting and in a murine melanoma model. Our novel vaccine construct contained the XCL1 ligand, to target uptake to XCR1 cross-presenting DC, and a cell penetrating peptide (CPP) with endosomal escape properties, to enhance antigen delivery into the cross-presentation pathway. Using a prime-boost regimen, we demonstrated robust expansion of antigen-specific T cells following vaccination with our CPP-linked peptide vaccine and protective immunity against HSV-1 skin infection, where vaccine epitopes were natively expressed by the virus. Additionally, our novel vaccination strategy slowed tumor outgrowth in a B16 murine melanoma model, compared to adjuvant only controls, suggesting antigen-specific anti-tumor immunity was generated following vaccination. These findings suggest that novel strategies to target the antigen cross-presentation pathway in DC may be beneficial for the generation of anti-tumor immunity.
交叉呈递树突状细胞（DC）因其具有将外源性抗原加工处理后呈递于MHC I类分子上的独特能力，成为了一种颇具吸引力的疫苗接种靶点。最近的报道证实，这些DC表达独特的表面受体，并在抗肿瘤免疫的启动过程中发挥关键作用，为开发特异性靶向这些细胞的疫苗接种策略开辟了道路。本研究调查了通过两种互补机制靶向交叉呈递DC是否能够在病毒感染背景以及小鼠黑色素瘤模型中提高疫苗效力。我们的新型疫苗构建体包含XCL1配体，用于靶向XCR1交叉呈递DC的摄取，以及一种具有内体逃逸特性的细胞穿透肽（CPP），以增强抗原向交叉呈递途径的递送。通过采用初免-加强免疫方案，我们证明在用与CPP连接的肽疫苗接种后，抗原特异性T细胞得到强劲扩增，并对HSV-1皮肤感染产生了保护性免疫，其中疫苗表位由病毒天然表达。此外，与仅使用佐剂的对照组相比，我们的新型疫苗接种策略减缓了B16小鼠黑色素瘤模型中的肿瘤生长，表明接种疫苗后产生了抗原特异性抗肿瘤免疫。这些发现表明，靶向DC中抗原交叉呈递途径的新策略可能有助于产生抗肿瘤免疫。
