Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation.
Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8(+) T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8(+) cells, as well as increased numbers of CD8(+) cells producing interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell-receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.
Jenq
Robert R
RR
Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
King
Christopher G
CG
Volk
Christine
C
Suh
David
D
Smith
Odette M
OM
Rao
Uttam K
UK
Yim
Nury L
NL
Holland
Amanda M
AM
Lu
Sydney X
SX
Zakrzewski
Johannes L
JL
Goldberg
Gabrielle L
GL
Diab
Adi
A
Alpdogan
Onder
O
Penack
Olaf
O
Na
Il-Kang
IK
Kappel
Lucy W
LW
Wolchok
Jedd D
JD
Houghton
Alan N
AN
Perales
Miguel-Angel
MA
van den Brink
Marcel R M
MR
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods / Q000401:mortality; D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D019496:Cancer Vaccines / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D019444:Vaccines, DNA / Q000276:immunology*
D015704:CD4 Antigens; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019444:Vaccines, DNA; D051523:Fibroblast Growth Factor 7