Tumor rejection by modulation of tumor stromal fibroblasts.
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.
Schüler
Thomas
T
German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. T.Schueler@dkfz-heidelberg.de
Körnig
Sandra
S
Blankenstein
Thomas
T
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000473:pathology; D002450:Cell Communication; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D015847:Interleukin-4 / Q000276:immunology*; D051379:Mice; D009368:Neoplasm Transplantation; D010954:Plasmacytoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
D019948:Receptors, Interleukin-4; D015847:Interleukin-4