Progenipoietin-generated dendritic cells exhibit anti-tumor efficacy in a therapeutic murine tumor model.
Progenipoietin (ProGP-4) is a chimeric molecule, exhibiting both Flt-3 and granulocyte-colony stimulating factor (G-CSF) receptor agonist activities. Subcutaneous administration of ProGP-4 to BALB/c mice at a dose of 40-100 microg/day for up to 12 consecutive days induces both CD11c(+) dendritic cells (DCs) and CD11c(-)/CD11b(+) granulocytes in spleen, blood and lymph nodes of treated animals. Peak numbers of all cell populations were observed on day 7 of treatment, with CD11c(+) DCs representing approximately 8% of total splenocytes at that time. Approximately 40-50% of these CD11c(+) cells were also able to endocytose and process the exogenous fluorescent antigen DQ-BSA. As a test of their therapeutic utility, freshly prepared CD11c(+) DCs were pulsed with a defined tumor-associated peptide epitope (murine p53(232-240)) and injected as a vaccine into BALB/c mice bearing day 7 established CMS4 sarcomas. Similarly prepared DCs were injected again 1 week later. Based on our results, we conclude that (i) both peptide-pulsed CD11c(+) DCs (harvested directly from ProGP-4 treated mice) and pulsed bone marrow-derived DCs effectively slow the growth of or mediate the regression (in 25 of 89 [28%] cases) of CMS4 tumors, and (ii) nonpulsed DCs mediated minimal or no therapeutic effect. These data support the ability of ProGP-4 to enhance the peripheral frequencies of DCs that exhibit therapeutic efficacy when applied as a vaccine to treat tumor-bearing animals.
Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. bjorckp@msx.upmc.edu
Pia
P
Björck
Wen-Rong
WR
Lie
Susan L
SL
Woulfe
Barbara K
BK
Klein
Walter
W
Olson
Walter J
WJ
Storkus
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003115:Colony-Stimulating Factors / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins; D012509:Sarcoma / Q000276:immunology*; D013997:Time Factors
D003115:Colony-Stimulating Factors; D011994:Recombinant Proteins; C434603:progenipoietin-1