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.