In situ vaccination via tissue-targeted cDC1 expansion enhances the immunogenicity of chemoradiation and immunotherapy

Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creatinga medical need. In cancer, DCs are indispensable forT cell activation, sothere is a restriction on cytotoxic T cell immunity if DCs are not present in...

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Published in:The Journal of clinical investigation 2024-01, Vol.134 (1), p.1-16
Main Authors: Lam, Brandon, Kung, Yu Jui, Lin, John, Tseng, Ssu-Hsueh, Tu, Hsin-Fang, Huang, Claire, Lee, Brandon, Velarde, Esteban, Tsai, Ya Chea, Villasmil, Rafael, Park, Sung Taek, Xing, Deyin, Hung, Chien-Fu, Wu, T-C
Format: Article
Language:English
Subjects:
Antigens
Apoptosis
Biomedical research
Cancer
Cancer therapies
Cancer vaccines
Cell activation
Cells
Chemoradiotherapy
Chemotherapy
Cytotoxicity
FLT3L protein
Half-life
Human papillomavirus
Immune checkpoint inhibitors
Immunity
Immunogenicity
Immunotherapy
Kinases
Ligands
Lymph nodes
Lymphatic system
Lymphocytes
Lymphocytes T
Mutation
Neoantigens
PD-L1 protein
Pharmacokinetics
Protein-tyrosine kinase
Proteins
Radiation therapy
Spleen
Tumors
Vaccination
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Summary:Even with the prolific clinical use of next-generation cancer therapeutics, many tumors remain unresponsive or become refractory to therapy, creatinga medical need. In cancer, DCs are indispensable forT cell activation, sothere is a restriction on cytotoxic T cell immunity if DCs are not present in sufficient numbers in the tumor and draining lymph nodes to take up and present relevant cancer antigens. To address this bottleneck, we developed a therapeutic based on albumin fused with FMS-related tyrosine kinase 3 ligand (Alb-Flt3L) that demonstrated superior pharmacokinetic properties compared with Flt3L, including significantly longer half-life, accumulation in tumors and lymph nodes, and cross-presenting-DC expansion following a single injection. We demonstrated that Alb-Flt3L, in combination with standard-of-care chemotherapy and radiation therapy, serves as an in situ vaccination strategy capable of engendering polyclonal tumor neoantigen-specific immunity spontaneously. In addition, Alb-Flt3L-mediated tumor control synergized with immune checkpoint blockade delivered as anti-PD-L1. The mechanism of action of Alb-Flt3L treatment revealed a dependency on Batf3, type I IFNs, and plasmacytoid DCs. Finally, the ability of Alb-Flt3Lto expand human DCs was explored in humanized mice. We observed significant expansion of human cross-presenting-DC subsets, supportingthe notion that Alb-Flt3L could be used clinically to modulate human DC populations in future cancertherapeutic regimens.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI171621.