Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes

Abstract

Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip⁺) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8⁺ T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip⁺ in tumor vaccines. Following immunization with 1V209-Cho-Lip⁺+OVA, we observed a pronounced "depot effect" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip⁺+OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip⁺+OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.