A scaffold vaccine to promote tumor antigen cross-presentation via sustained toll-like receptor-2 (TLR2) activation

• Published in: Bioactive materials Vol. 37; pp. 315 - 330
• Main Authors: Xie, Daping, Han, Congwei, Chen, Chonghao, Liao, Zhencheng, Campos de Souza, Senio, Niu, Yiming, Mano, João F., Dong, Lei, Wang, Chunming
• Format: Journal Article
• Language: English
• Published: China Elsevier B.V 01.07.2024; KeAi Publishing Communications Ltd; KeAi Publishing; KeAi Communications Co., Ltd
• Subjects: Adjuvants; Antigen (tumor-associated); Antigen presentation; Antigen-presenting cells; Antigens; Cancer; Cancer therapies; Cancer vaccines; CD8 antigen; Cell activation; Chemical synthesis; Colorectal carcinoma; Cross-presentation; Cytokines; Cytotoxicity; Dendritic cells; Effectiveness; Hyaluronic acid; Hydrophobicity; Lung cancer; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medical research; Metastases; Molecular weight; Ovalbumin; Polysaccharide; Polysaccharides; Reactive oxygen species; Scaffold vaccine; Scaffolds; TLR2 agonist; TLR2 protein; Toll-like receptors; Transgenic mice; Tumors; Vaccines; United States > US; China; Cross-presentation; Reactive oxygen species; Scaffold vaccine; TLR2 agonist; Polysaccharide
• ISSN: 2452-199X; 2097-1192; 2452-199X
• DOI: 10.1016/j.bioactmat.2024.03.035

Cancer vaccination holds great promise for cancer treatment, but its effectiveness is hindered by suboptimal activation of CD8+ cytotoxic T lymphocytes, which are potent effectors to mediate anti-tumor immune responses. A possible solution is to switch antigen-presenting cells to present tumor antigens via the major histocompatibility complex class I (MHC-I) to CD8+ T cells – a process known as cross-presentation. To achieve this goal, we develop a three-dimensional (3D) scaffold vaccine to promote antigen cross-presentation by persisted toll-like receptor-2 (TLR2) activation after one injection. This vaccine comprises polysaccharide frameworks that “hook” TLR2 agonist (acGM) via tunable hydrophobic interactions and forms a 3D macroporous scaffold via click chemistry upon subcutaneous injection. Its retention-and-release of acGM enables sustained TLR2 activation in abundantly recruited dendritic cells in situ, inducing intracellular production of reactive oxygen species (ROS) in optimal kinetics that crucially promotes efficient antigen cross-presentation. The scaffold loaded with model antigen ovalbumin (OVA) or tumor specific antigen can generate potent immune responses against lung metastasis in B16-OVA-innoculated wild-type mice or spontaneous colorectal cancer in transgenic ApcMin/+ mice, respectively. Notably, it requires neither additional adjuvants nor external stimulation to function and can be adjusted to accommodate different antigens. The developed scaffold vaccine may represent a new, competent tool for next-generation personalized cancer vaccination. A scaffold vaccine that promotes antigen cross-presentation to trigger CD8+T cell-mediated anti-tumor immune responses. In this study, we discover that the kinetics of intracellular ROS, unexpectedly, dictates the mode of antigen presentation. Persistent production in moderate dose promotes antigen cross-presentation. To create optimal intracellular ROS kinetics for lysosomal disruption and antigen escape, we design a 3D injectable scaffold for the “retention-and-release” of a TLR2 agonist glycan upon subcutaneous implantation. Installation of tunable hydrophobic interactions between the scaffold and the “hooked” agonist enables sustained TLR activation in the abundantly recruited DCs in situ, which triggers consequently efficient cross-presentation of tumor antigens. The efficacy of this novel scaffold vaccine is subsequently undergoing comprehensive evaluations in both wild-type and transgenic mice against localized, metastatic, and spontaneous tumors. [Display omitted] •Intracellular ROS kinetics dictates antigen-presenting mode.•Sustained TLR2 activation triggers intracellular ROS kinetics required for cross-presentation.•A scaffold vaccine enabling “retention-and-release” for sustained TLR2 activation in DCs promotes cross-presentation.•The scaffold vaccine induces robust, CD8+ T cells-mediated anti-tumor immune responses in Apcmin/+ transgenic mice.