Barber R G, Cherry Steven, Stephens Sydney, Mann Kristine, Martinson Holly A, Kullberg Max
WWAMI School of Medical Education, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA.
Department of Biological Sciences, University of Alaska Anchorage, 3211 Providence Drive, Anchorage, AK 99508, USA.
Int J Mol Sci. 2025 May 22;26(11):4985. doi: 10.3390/ijms26114985.
The activation of immunosuppressed antigen-presenting cells (APCs) in the tumor microenvironment is a key goal in modern cancer immunotherapy. Our laboratory utilizes a liposome-based immunotherapy platform that binds endogenous complement to deliver antigen, adjuvant, and therapeutic agents to APCs in vivo. The liposomes contain external linker groups, which readily bind complement protein C3, and mediate liposomal uptake via complement receptor 3 into APCs. To test the ability of a model antigen to bind to these external linker groups on C3-liposomes and elicit a robust adaptive immune response, we conjugated a modified ovalbumin peptide (OVA-C) to the liposomes and incorporated a toll-like receptor (TLR) 4 agonist, monophosphoryl lipid A (MPLA), in the liposomal membrane. Adaptive immune responses from C57BL/6 mice were analyzed by ELISA and ELISpot. Mice vaccinated with OVA-C liposomes elicited significantly greater humoral and cellular adaptive responses relative to controls. Furthermore, female mice vaccinated with MPLA + OVA-C liposomes produced significantly more IgG antibodies than males vaccinated with the same liposomes. In conclusion, antigen binding on the exterior of C3-liposomes markedly improves antigen loading efficiency and still allows for complement C3-targeted delivery to APCs. These data demonstrate the initiation of a robust cellular and humoral immune response using a new liposomal delivery platform.
激活肿瘤微环境中免疫抑制的抗原呈递细胞（APC）是现代癌症免疫疗法的关键目标。我们实验室利用基于脂质体的免疫疗法平台，该平台结合内源性补体，以便在体内将抗原、佐剂和治疗剂递送至APC。这些脂质体含有外部连接基团，其易于结合补体蛋白C3，并通过补体受体3介导脂质体被APC摄取。为了测试模型抗原与C3脂质体上这些外部连接基团结合并引发强大适应性免疫反应的能力，我们将修饰的卵清蛋白肽（OVA-C）偶联到脂质体上，并在脂质体膜中掺入Toll样受体（TLR）4激动剂单磷酰脂质A（MPLA）。通过ELISA和ELISpot分析C57BL/6小鼠的适应性免疫反应。与对照组相比，用OVA-C脂质体接种的小鼠引发了显著更强的体液和细胞适应性反应。此外，用MPLA + OVA-C脂质体接种的雌性小鼠产生的IgG抗体明显多于用相同脂质体接种的雄性小鼠。总之，C3脂质体外部的抗原结合显著提高了抗原负载效率，并且仍然允许将补体C3靶向递送至APC。这些数据证明了使用新的脂质体递送平台引发强大的细胞和体液免疫反应。
