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.
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.
Liu
Yongqing
Y
Departments of Microbiology and Pathology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 0W0.
Huang
Hui
H
Chen
Zhuang
Z
Zong
Li
L
Xiang
Jim
J
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000378:metabolism; D000818:Animals; D019496:Cancer Vaccines; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D005260:Female; D006801:Humans; D007107:Immune System / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D018925:Chemokines; D016207:Cytokines; D008565:Membrane Proteins; C084881:flt3 ligand protein