Restoration of Tumor Immunosurveillance via Targeting of Interleukin-13 Receptor-α2

Abstract

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-B 1 (TGF-B 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-13RA 2 , on Gr-1 intermediate cells, because downregulation of IL-13RA 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-B 1 production. Furthermore, acting on prior studies showing that IL-13RA 2 expression is induced (in part) by tumor necrosis factor-A (TNF-A), we show that receptor expression and TGF-B 1 production is inhibited by administration of a TNF-A-neutralizing substance, TNF-ARFc (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-AR-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. [Cancer Res 2008;68(9):3467-75]

A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer

“…It was assumed that lung metastasis was not significantly enhanced following etanercept treatment in the present study, as etanercept exhibited little effect on NK cells. This finding does not conflict with previous studies reporting that TNF blockade inhibits carcinogenesis and cancer metastasis (41,42).…”

“…Etanercept has been reported to reduce the number and size of tumors in a spontaneous colon cancer mouse model associated with chronic colitis (40). Furthermore, blockade of TNF-α has been reported to inhibit lung metastasis in a mouse model (41,42). Concerning the effect of etanercept on NK cells, etanercept was reported to inhibit the production of transforming growth factor (TGF)-β1, which subsequently led to the inhibition of NK cells and cytotoxic activity (42).…”

“…Furthermore, blockade of TNF-α has been reported to inhibit lung metastasis in a mouse model (41,42). Concerning the effect of etanercept on NK cells, etanercept was reported to inhibit the production of transforming growth factor (TGF)-β1, which subsequently led to the inhibition of NK cells and cytotoxic activity (42). In an experimental lung metastasis mouse model, etanercept inhibited TGF-β1 production, which induced IL-13, restored CD8 + cell cytolytic activity and reduced lung metastasis (42).…”

“…Concerning the effect of etanercept on NK cells, etanercept was reported to inhibit the production of transforming growth factor (TGF)-β1, which subsequently led to the inhibition of NK cells and cytotoxic activity (42). In an experimental lung metastasis mouse model, etanercept inhibited TGF-β1 production, which induced IL-13, restored CD8 + cell cytolytic activity and reduced lung metastasis (42). In the present study, there was a significant decrease in the percentage of CD11b + CD27 -NK cells in the spleen following treatment with etanercept compared with that in other groups.…”

Myeloid-derived suppressor cells and myeloid regulatory cells in cancer and autoimmune disorders

“…Notably, a previous study demonstrated that CD11b + Gr-1 + cells isolated from mice with EAE inhibited T cell proliferation in co-culture with naive CD4 cells, but promoted Th17 cell differentiation under Th17-polarizing conditions (71). Another study demonstrated that activation of the suppressive function of M-MDSCs occurred at the peak of EAE disease (72). This aforementioned study determined that the suppression of T cell responses was due to M-MDSC-mediated NO production (72).…”