The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published 17 November 2003. doi:10.1084/jem.20030849
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© Rockefeller University Press, 0022-1007/2003/11/1487 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1487-1493

Tumor Rejection by Modulation of Tumor Stromal Fibroblasts

Thomas Schüler1, Sandra Körnig1 and Thomas Blankenstein1,2

1 Max-Delbrück-Centrum for Molecular Medicine, 13092 Berlin, Germany
2 Institute of Immunology, Free University Berlin, 12200 Berlin, Germany

Address correspondence to Thomas Schüler, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Phone: 49-6221-423732; Fax: 49-6221-401629; email: T.Schueler{at}dkfz-heidelberg.de

Interleukin (IL)-4–secreting tumors are rejected in mice, an effect that is thought to be immune mediated. However, solid tumors are embedded in a stroma that often contains tumor-promoting fibroblasts, a cell population whose function is also affected by IL-4. Here we show that IL-4–secreting tumors grew undiminished in IL-4 receptor (R)–deficient (IL-4R-/-) mice. In IL-4R+/+ mice they were long-term suppressed in the absence of T cells but complete rejection required T cells, compatible with the assumption that hematopoietic cells needed to respond to IL-4. Surprisingly, bone marrow (BM) chimeric mice revealed that IL-4R expression exclusively on non-BM–derived cells was sufficient for tumor rejection. Fibroblasts in the tumor stroma were identified as a target cell type for IL-4 because they accumulated in IL-4–secreting tumors and displayed an activated phenotype. Additionally, coinjection of IL-4R+/+ but not IL-4R-/- fibroblasts was sufficient for the rejection of IL-4–secreting tumors in IL-4R-/- mice. Our data demonstrate a novel mechanism by which IL-4 contributes to tumor rejection and show that the targeted modulation of tumor-associated fibroblasts can be sufficient for tumor rejection.

Key Words: IL-4 receptor • knockout mice • bone marrow transplantation • angiogenesis • collagen


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