Tumor-derived interleukin-4 reduces tumor clearance and deviates the cytokine and granzyme profile of tumor-induced CD8+ T cells.
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.
Olver
Stuart
S
Cooperative Research Centre for Vaccine Technology, Brisbane, Queensland, Australia.
Groves
Penny
P
Buttigieg
Kathy
K
Morris
Edward S
ES
Janas
Michelle L
ML
Kelso
Anne
A
Kienzle
Norbert
N
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D015236:HLA-C Antigens / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D034801:Mastocytoma / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D015236:HLA-C Antigens; C038653:HLA-C*03 antigen; D015847:Interleukin-4