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.