Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China.
Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
Acta Biomater. 2023 Nov;171:482-494. doi: 10.1016/j.actbio.2023.09.013. Epub 2023 Sep 13.
Therapeutic cancer nanovaccines can induce strong antitumor immunity and establish long-term immune memory and have shown potential for curing tumors in some clinical trials. However, weak immunogenicity and safety concerns of nanocarriers limit the clinical translation of some therapeutic nanovaccines. Here, we developed minimal-component cancer nanovaccines, monophosphoryl lipid A (MPLA)-assembled nanovaccines (MANs), that could facilitate the clinical application of nanovaccines. The MANs were formed by protein antigens extracted from chemotherapy-induced tumor cell cultures and the amphiphilic immune adjuvant MPLA. Compared with free chemotherapy-induced antigens, MANs can activate the Toll-like receptor 4 (TLR4)-mediated signalling pathway and promote adaptive immunity against tumor antigens. Mechanistic analysis indicated that MANs induced antigen capture of DCs and promoted the activation of DCs and T cells, thereby optimizing the ratio of CD8 T/Tregs in tumors and facilitating the transformation of the tumor immune microenvironment (TIME) from "cold" to "hot". In a CT26 colorectal cancer model, MANs+αPD-1 significantly improved the efficacy of αPD-1 treatment. Our work offers a strategy for designing minimal-component cancer nanovaccines with potential clinical benefits. STATEMENT OF SIGNIFICANCE: To address the weak immunogenicity of cancer vaccines and the safety concerns of nanocarriers, we prepared MPLA-assembled nanovaccines (MANs) using chemotherapy induced antigens and the immune adjuvant MPLA to promote cancer vaccines to clinical practice. MANs effectively internalized tumor antigens and induced DC maturation, indicating that the initial anti-tumor response had been activated. MANs+αPD-1 induced APCs, CD8 T cells and memory T cells with positive anti-tumor effects to migrate to tumor tissue, thus leading to the transformation of the tumor immune microenvironment from "cold" to "hot". At the animal level, the combination of MANs and αPD-1 exerted synergistic effects and significantly enhanced tumor immunotherapy. Therefore, the treatment regimen of MANs+αPD-1 has potential clinical benefits.
治疗性癌症纳米疫苗可以诱导强烈的抗肿瘤免疫，建立长期免疫记忆，并在一些临床试验中显示出治愈肿瘤的潜力。然而，纳米载体的弱免疫原性和安全性问题限制了一些治疗性纳米疫苗的临床转化。在这里，我们开发了最小成分的癌症纳米疫苗，即单磷酰脂质 A（MPLA）组装的纳米疫苗（MANs），这可以促进纳米疫苗的临床应用。MANs由化疗诱导的肿瘤细胞培养物中提取的蛋白质抗原和两亲性免疫佐剂 MPLA 组成。与游离的化疗诱导抗原相比，MANs 可以激活 Toll 样受体 4（TLR4）介导的信号通路，促进对肿瘤抗原的适应性免疫。机制分析表明，MANs 诱导 DC 摄取抗原，并促进 DC 和 T 细胞的激活，从而优化肿瘤中 CD8 T/Tregs 的比例，并促进肿瘤免疫微环境（TIME）从“冷”到“热”的转变。在 CT26 结直肠癌细胞模型中，MANs+αPD-1 显著提高了 αPD-1 治疗的疗效。我们的工作为设计具有潜在临床益处的最小成分癌症纳米疫苗提供了一种策略。
