Immunotherapy with interleukin-10 depends on the CXC chemokines inducible protein-10 and monokine induced by IFN-gamma.
The cytokine interleukin (IL)-10 has potent antitumor activity in many model systems when expressed locally at very high levels from the time of tumor transplantation. We now demonstrate that systemic administration of recombinant human IL-10 to animals bearing established highly malignant mammary tumors also leads to significant growth inhibition. We had shown previously that expression of the CXC chemokines Mig (monokine induced by IFN-gamma) and IP-10 (inducible protein 10) is observed in IL-10 transduced but not neo-vector control tumors. We now demonstrate that treatment of IL-10-tumor-bearing mice with antibodies to either chemokine partially reverses the therapeutic effect of IL-10. Tumor growth in animals treated with both antibodies is comparable with that of vector control tumors. Direct transduction of Mig cDNA into the parental tumor cell line before transplantation also results in smaller tumors. This tumor growth inhibition is associated with increased numbers of CD4+ cells, consistent with a T-cell chemoattractant activity for Mig. No change in vascularization, as indicated by CD31+ cells, was observed in either Mig or IL-10-transfected tumors. Thus, an antiangiogenic activity for either cytokine could not be confirmed. Mig and IP-10 are critical to the therapeutic response resulting from high levels of IL-10, and, furthermore, Mig as a single agent also has tumor-inhibitory activity in a model of breast cancer.
Dorsey
Russell
R
Department of Pathology, University of Maryland, Baltimore, Maryland 21201, USA.
Kundu
Namita
N
Yang
Qingyuan
Q
Tannenbaum
Charles S
CS
Sun
Hui
H
Hamilton
Thomas A
TA
Fulton
Amy M
AM
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology*; D007167:Immunotherapy; D036341:Intercellular Signaling Peptides and Proteins; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D014161:Transduction, Genetic; D014162:Transfection
C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D016753:Interleukin-10