The effect of T1 and T2 cytokines on the cytotoxic T cell response to mannan-MUC1.
MUC1 is a mucin over-expressed in breast cancer and a proposed target for immunotherapy. By immunising mice with MUC1 conjugated to mannan (M-FP), CD8(+) MHC-class-I restricted cytotoxic T lymphocytes (CTL), of high CTL precursor (CTLp) frequency (1/8000) and with significant tumour protection, can be induced. The effect of various cytokines [interleukin-2 (IL-2), IL-4, IL-6, IL-7, interferon gamma (IFNgamma), and granulocyte/macrophage-colony-stimulating factor (GM-CSF)] on the MUC1 CTL immune response was investigated (a) by measuring the frequencies of CTLp in mice immunised with vaccinia virus constructs containing recombinant cytokines and M-FP, or (b) by immunising cytokine- or cytokine-receptor-knockout (-/-) mice with M-FP. Vaccinia virus (VV) constructs containing recombinant cytokines were used either individually or in combination in vivo with M-FP immunisation. M-FP immunisations combined with VV-IL-2, VV-IL-7 and VV-GM-CSF, and combinations of VV-IFNgamma + VV-IL-2, VV-IFNgamma + VV-IL-4 or VV-GM-CSF + VV-IL-7 increased CTLp frequencies up to threefold (1/17 666: M-FP + VV-GM-CSF + VV-IL-7) compared to M-FP (1/77 500) alone. By contrast, M-FP combined with VV-IL-4 decreased the CTLp frequency threefold whereas VV-IL-6 and VV-IFNgamma had no effect. Studies in cytokine- and cytokine-receptor-gene-knockout (-/-) mice demonstrated that mice that are IL-2 -/- and IL-7 receptor -/- produce the same CTLp response to M-FP as do control mice, whereas responses in the IL-6 -/-, IL-10 -/- and IFNgamma -/- mice were marginally improved and responses to M-FP in IL-4 -/- and tumour necrosis factor receptor 2 -/- mice were weaker. In spite of the increase in CTLp frequency, this was not reflected in an in vivo tumour model. Tumour challenges using MUC1(+) P815 cells, demonstrated that the addition of cytokines had little additive effect on the already effective tumour-regression capabilities of M-FP alone.
Lees
C J
CJ
Austin Research Institute, Studley Road, Heidelberg, Vic. 3084 Australia.
Apostolopoulos
V
V
Acres
B
B
Ong
C S
CS
Popovski
V
V
McKenzie
I F
IF
D000595:Amino Acid Sequence; D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007114:Immunization; D007167:Immunotherapy; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D008351:Mannans / Q000008:administration & dosage; D012515:Mast-Cell Sarcoma / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000008:administration & dosage / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D014616:Vaccinia virus
D016207:Cytokines; D007376:Interleukin-2; D015850:Interleukin-6; D015851:Interleukin-7; D008351:Mannans; D018396:Mucin-1; D018121:Receptors, Cytokine; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor