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.

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-1beta and chemokines MIP-1alpha, MIP-1beta, 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 x 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 x 10(5)) 3LL tumor cells (p < 0.01).

CONCLUSIONS:

DCs engineered to secrete Flt3L may offer a new strategy in DC-based cancer vaccines.

• Authors: Yongqing Liu, Hui Huang, Zhuang Chen, Li Zong, Jim Xiang
• Journal: The journal of gene medicine (J Gene Med) Vol. 5 Issue 8 Pg. 668-80 (Aug 2003) ISSN: 1099-498X [Print] England
• PMID: 12898636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2003 John Wiley & Sons, Ltd.

Chemical References

• Adjuvants, Immunologic
• Cancer Vaccines
• Chemokines
• Cytokines
• Membrane Proteins
• flt3 ligand protein

Topics

• Adenoviridae (genetics, metabolism)
• Adjuvants, Immunologic (metabolism)
• Animals
• Cancer Vaccines
• Cell Line, Tumor
• Cell Movement (physiology)
• Chemokines (metabolism)
• Cytokines (metabolism)
• Dendritic Cells (immunology, physiology)
• Female
• Humans
• Immune System (physiology)
• Killer Cells, Natural (immunology, metabolism)
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neoplasms (immunology, metabolism)
• Survival Rate
• T-Lymphocytes (cytology, metabolism)
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Transgenes