Electroporation-mediated novel albumin-fused Flt3L DNA delivery promotes cDC1-associated anticancer immunity

Ming-Hung Hu; Darrell Fan; Hsin-Fang Tu; Ya-Chea Tsai; Liangmei He; Zhicheng Zhou; Michelle Cheng; Deyin Xing; Suyang Wang; Alexis Wu; T C Wu; Chien-Fu Hung

doi:10.1038/s41434-024-00497-3

Electroporation-mediated novel albumin-fused Flt3L DNA delivery promotes cDC1-associated anticancer immunity

Gene Ther. 2024 Oct 29. doi: 10.1038/s41434-024-00497-3. Online ahead of print.

Authors

Ming-Hung Hu^{1

2

3

4}, Darrell Fan¹, Hsin-Fang Tu¹, Ya-Chea Tsai¹, Liangmei He¹, Zhicheng Zhou¹, Michelle Cheng¹, Deyin Xing¹, Suyang Wang¹, Alexis Wu¹, T C Wu^{1

5

6

7}, Chien-Fu Hung^{8

9}

Affiliations

¹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
³ Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC.
⁴ Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, ROC.
⁵ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁶ Department of Obstetrics and Gynecology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Molecular Microbiology and Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁸ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
⁹ Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].

PMID: 39472678
DOI: 10.1038/s41434-024-00497-3

Abstract

Dendritic cells (DCs) constitute a distinct type of immune cell found within tumors, serving a central role in mediating tumor antigen-specific immunity against cancer cells. Frequently, DC functions are dysregulated by the immunosuppressive signals present within the tumor microenvironment (TME). Consequently, DC manipulation holds great potential to enhance the cytotoxic T cell response against cancer diseases. One strategy involves administering Fms-like tyrosine kinase receptor 3 ligand (Flt3L), a vitally important cytokine for DC development. In this current study, the electroporation-mediated delivery of a novel albumin-fused Flt3L DNA (alb-Flt3L DNA) demonstrated the ability to induce an anti-tumor immune response. This albumin fusion construct possesses more persistent bioactivity in targeted organs. Furthermore, TC-1-bearing-C57BL/6 mice receiving alb-Flt3L DNA treatment presented better tumor control and superior survival. Cellular analysis revealed that alb-Flt3L DNA administration promoted robust DC and cDC1 expansion. In addition, increased levels of IFN-γ-secreting CD8⁺ lymphocytes were found in correlation to greater cDC1 population. Moreover, the toxicity of alb-Flt3L administration is limited. Collectively, our data showcases a novel DC-based immunotherapy using electroporation to administer alb-Flt3L DNA.

Abstract

Grants and funding