Dendritic cells engineered to express the Flt3 ligand stimulate type I immune response, and induce enhanced cytoxic T and natural killer cell cytotoxicities and antitumor immunity

✍ Scribed by Yongqing Liu; Hui Huang; Zhuang Chen; Li Zong; Dr Jim Xiang

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 284 KB
• Volume: 5
• Category: Article
• ISSN: 1099-498X
• DOI: 10.1002/jgm.387

✦ Synopsis

Abstract

Background

Tumor antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of antitumor immune responses. Fms‐like tyrosine kinase 3 ligand (Flt3L) is a regulator of hematopoietic cell development.

Methods

To investigate the potential effect of Flt3L transgene expression on DC‐based cancer vaccines, we constructed a recombinant adenovirus AdVFlt3L expressing Flt3L, transfected DCs with AdVFlt3L, and investigated the efficacy of antitumor immunity by vaccination of DC~Flt3L~ engineered to express Flt3L transgene.

Results

Our data demonstrated that AdVFlt3L transfection up‐regulated the expression of cytokine IL‐1β and chemokines MIP‐1α, MIP‐1β, IP‐10, MCP‐1 and MIP‐2, and stimulated DC~Flt3L~ cell proliferation in vitro and migration toward regional lymph nodes in vivo. Our data also demonstrated that vaccination of Mut1‐pulsed DC~Flt3L~ cells was able to stimulate (i) a type 1 immune response comprising CD4^+^ Th1 and CD8^+^ Tc1 activation and (ii) around 2‐ and 3‐fold enhanced tumor‐specific cytotoxic T lymphocyte (CTL) and non‐specific NK responses (p < 0.05) than vaccination with similarly pulsed control virus‐transfected and untransfected DCs, respectively. More importantly, vaccination of Mut1‐pulsed DC~Flt3L~ cells induced enhanced antitumor immunity in vivo, even against poorly immunogenic 3LL tumor cells. Vaccinations of Mut1‐pulsed DCs, DC~pLpA~ and DC~Flt3L~ all protected mice from challenge of low dose (0.5 × 10^5^) tumor cells. However, only vaccination of the last one was able to protect 63% (6/8) mice from challenge of high dose (3 × 10^5^) 3LL tumor cells (p < 0.01).

Conclusions

DCs engineered to secrete Flt3L may offer a new strategy in DC‐based cancer vaccines. Copyright © 2003 John Wiley & Sons, Ltd.