Restoration of tumor immunosurveillance via targeting of interleukin-13 receptor-alpha 2.
In previous studies, we described a "counter-immunosurveillance" mechanism initiated by tumor-activated, interleukin-13 (IL-13)-producing natural killer T cells that signal Gr-1(+) cells to produce transforming growth factor-beta(1) (TGF-beta(1)), a cytokine that suppresses the activity of tumor-inhibiting cytolytic CD8(+) T cells. Here, we show that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models), this counter-surveillance mechanism requires the expression of a novel IL-13 receptor, IL-13R alpha(2), on Gr-1(intermediate) cells, because down-regulation of IL-13R alpha(2) expression or the activator protein-1 signal generated by the receptor via in vivo administration of specific small interfering RNA or decoy oligonucleotides leads to loss of TGF-beta(1) production. Furthermore, acting on prior studies showing that IL-13R alpha(2) expression is induced (in part) by tumor necrosis factor-alpha (TNF-alpha), we show that receptor expression and TGF-beta(1) production is inhibited by administration of a TNF-alpha-neutralizing substance, TNF-alpha R-Fc (etanercept). Taking advantage of this latter fact, we then show in the CT-26 model that counter-immunosurveillance can be inhibited, anti-CT-26-specific CD8(+) cytolytic activity can be restored, and CT-26 metastatic tumor nodules can be greatly decreased by administration of TNF-alpha R-Fc. Corroborative data were obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent with already known clinically acceptable adverse effects and toxicity.
Fichtner-Feigl
Stefan
S
Department of Surgery, University of Regensburg, Regensburg, Germany. stefan.fichtner@klinik.uni-regensburg.de
Terabe
Masaki
M
Kitani
Atsushi
A
Young
Cheryl A
CA
Fuss
Ivan
I
Geissler
Edward K
EK
Schlitt
Hans-Jürgen
HJ
Berzofsky
Jay A
JA
Strober
Warren
W
D000818:Animals; D002277:Carcinoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D015536:Down-Regulation; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D007157:Immunologic Surveillance / Q000187:drug effects*; D018793:Interleukin-13 / Q000378:metabolism / Q000494:pharmacology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1