An all-in-one adjuvanted therapeutic cancer vaccine targeting dendritic cell cytosol induces long-lived tumor suppression through NLRC4 inflammasome activation
Sao Puth, Vivek Verma, Seol Hee Hong, Wenzhi Tan, Shee Eun Lee, Joon Haeng Rhee
Abstract
Therapeutic cancer vaccines (TCVs) should induce robust tumor-specific T cell responses. To achieve this, TCVs incorporate T cell epitopes and strong adjuvants. Here, we report an all-in-one adjuvanted cancer vaccine platform that targets the intracellular compartment of dentritic cells and subsequently induces effective cytotoxic T cell responses. We screened a novel peptide (DCpep6) that specifically binds and transmits into CD11c+ cells through a novel in vivo phage biopanning. We then engineered a protein-based TCV (DEF) consisting of DCpep6 (D), an optimized HPV E7 tumor antigen (E), and a built-in flagellin adjuvant (F) as a single molecule. DEF was stably expressed, and each component was functional. In vivo-administered DEF rapidly biodistributed in draining LNs and internalized into CD11c+ cells. DEF immunization elicited strong antitumor T cell responses and provided long-term survival of TC-1 tumor-implanted mice. The DEF-mediated antitumor effect was abolished in NLRC4−/− mice. Taken together, we propose a protein-based all-in-one TCV platform that intracellularly codelivers tumor antigen and inflammasome activator to DCs to induce long-lasting antitumor T cell responses.