Tumor-derived interleukin-4 reduces tumor clearance and deviates the cytokine and granzyme profile of tumor-induced CD8+ T cells.

Abstract

An interleukin (IL)-4-containing tumor environment is reported to be beneficial for immune clearance of tumor cells in vivo; however, the effect of IL-4 on the effector CD8+ T cells contributing to tumor clearance is not well defined. We have used the immunogenic HLA-CW3-expressing P815 (P.CW3) mastocytoma and investigated whether IL-4 expression by the tumor affects tumor clearance and, if so, whether it alters the tumor-induced Vbeta10+ CD8+ T-cell response. P.CW3 were stably transfected with IL-4 or the empty control vector, and independent cell lines were injected i.p. into syngeneic DBA/2 mice. After apparent clearance of primary tumors over 12 to 15 days, secondary tumors arose that lacked surface expression and H-2-restricted antigen presentation of CW3 in part due to the loss of the HLA-CW3 expression cassette. Surprisingly, mice that received IL-4-producing tumor cells showed delayed primary tumor clearance and were significantly more prone to develop secondary tumors compared with mice receiving control tumor cells. Tumor clearance was dependent on CD8+ T cells. The IL-4-secreting P.CW3 tumor cells led to markedly higher mRNA expression of IL-4 and granzyme A and B but no differences in IFN-gamma and IL-2 production, cell proliferation, or ex vivo CTL activity in primary Vbeta10+ CD8+ T cells when compared with the control tumor cells. We concluded that tumor-derived IL-4 selectively changed the quality of the tumor-induced CD8+ T-cell response and resulted in unexpected negative effects on tumor clearance. These data bring into question the delivery of IL-4 to the tumor environment for improving tumor immunotherapy.

• Authors: Stuart Olver, Penny Groves, Kathy Buttigieg, Edward S Morris, Michelle L Janas, Anne Kelso, Norbert Kienzle
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 1 Pg. 571-80 (Jan 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 16397274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-C Antigens
• HLA-C*03 antigen
• Interleukin-4

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Female
• Gene Expression
• HLA-C Antigens (immunology)
• Interleukin-4 (biosynthesis, genetics, immunology)
• Mastocytoma (genetics, immunology)
• Mice
• Mice, Inbred DBA
• T-Lymphocytes, Cytotoxic (immunology)
• Transfection