Anti-tumor activity of dendritic cells transfected with mRNA for receptor for hyaluronan-mediated motility is mediated by CD4+ T cells.
Receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in various tumors with high frequency, and was recently identified as an immunogenic antigen by serologic screening of cDNA expression libraries. In this study, we explored whether RHAMM is a potential target for dendritic cell (DC) immunotherapy. We constructed a plasmid for transduction of in vitro-transcribed mRNAs into DCs to efficiently transport the intracellular protein RHAMM into MHC class II compartments by adding a late endosomal/lysosomal sorting signal to the RHAMM gene. Immunization of mice with modified RHAMM mRNA-transfected DCs (DC/RHAMM) induced killing activity against RHAMM-positive tumor cells in splenocytes. To examine whether CD4(+) and/or CD8(+) T cells were required for this antitumor immunity, an anti-CD4 or anti-CD8 antibody was administered to mice after immunization with DC/RHAMM. Depletion of CD4(+) T cells significantly diminished the induction of tumor cell-killing activity in splenocytes, whereas CD8(+) T cell depletion had no effect. We then investigated the therapeutic effect of DC/RHAMM in a 3-day tumor model of EL4. DC/RHAMM was administered to mice on days 3, 7 and 10 after EL4 tumor inoculation. The treatment markedly inhibited tumor growth compared to control DCs. Moreover, antibody-mediated depletion of CD4(+) T cells completely abrogated the therapeutic effect of DC/RHAMM, whereas depletion of CD8(+) T cells had no effect. The results of this preclinical study indicate that DCs transfected with a modified RHAMM mRNA targeted to MHC class II compartments can induce CD4(+) T cell-mediated antitumor activity in vivo.
Fukui
Mikiko
M
Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, 1-1-1, Minami-Kogushi, Ube, 755-8505, Japan.
Ueno
Koji
K
Suehiro
Yutaka
Y
Hamanaka
Yuichiro
Y
Imai
Kohzoh
K
Hinoda
Yuji
Y
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006649:Histocompatibility Antigens / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology*; D012333:RNA, Messenger; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D016326:Extracellular Matrix Proteins; D006649:Histocompatibility Antigens; D018960:Hyaluronan Receptors; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C098946:hyaluronan-mediated motility receptor