Albumin-Flt3L-induced cross-presenting dendritic cells promote neoantigen-specific antitumor immunity and subsequent tumor control in murine models of cancer

Abstract

Abstract Central to the long-term success of essentially all cancer treatment strategies is the generation of durable tumor specific cytotoxic CD8+ T cell immunity, which requires uptake and potent antigen cross-presentation by dendritic cells (DCs) since tumor cells do not efficiently present relevant CD8+ T cell epitopes. FMS-like tyrosine kinase 3 ligand (Flt3L) is a cytokine that expands and differentiates DC precursors to murine cross-presenting CD103+ and CD8a+ DCs, but the therapeutic potential of Flt3L is limited because of its short half-life and global distribution in vivo. We have overcome the described issues by generating a novel genetic fusion of Albumin (Alb) to Flt3L, named Albumin-Flt3L (Alb-Flt3L), since Alb has a long half-life and exhibits trafficking to the lymph node (LN) and tumor (TM) as a serum protein. The novel immunotherapeutic Alb-Flt3L fusion protein exhibits increased half-life measured by ELISA, selective accumulation in LN and TM by IVIS imaging compared to native Flt3L, and potently expands cross-presenting DCs with no detectable toxicities. Challenging mice with HPV-associated TC-1 and MC38 adenocarcinoma tumor model, Alb-Flt3L + targeted radiation therapy to release tumor antigen and enhance tumor immunogenicity is able to control tumor progression and extend survival. When analyzing the immune response in mice challenged with MC38 tumor, significant intratumoral neoantigen specific CD8+ T cell responses are seen by tetramer staining, suggesting that Alb-Flt3L expanded DCs are able to engender neoantigen specific T cells without additional peptide vaccination. The therapeutic potential, mechanism of action, and subsequent implications of Alb-Flt3L use are under further investigation.