Tumors have evolved elaborate mechanisms for evading immune detection, such as production of immunoinhibitory cytokines and down-regulation of major histocompatibility complex (MHC) expression. We have studied PAX3-FKHR as an example of an oncogenic fusion protein associated with an aggressive metastatic cancer. We show that PAX3-FKHR alters expression of genes that are normally regulated by Janus kinase/signal transducer and activator of transcription (STAT) signaling pathways. This occurs as a result of a specific interaction between PAX3-FKHR and the STAT3 transcription factor, which results in a dramatic reduction in tumor MHC expression, and an alteration in local cytokine concentrations to inhibit surrounding inflammatory cells and immune detection. Collectively, these data show that an oncogenic transcription factor can promote tumor growth and tissue invasion while inhibiting local inflammatory and immune responses. This is the first time that an immunomodulatory role has been described for an oncogenic fusion protein.

Rhabdomyosarcoma (RMS) is an aggressive tumor resembling developing skeletal muscle that predominantly affects children (1). PAX3-FKHR is an oncogenic fusion protein and is specifically associated with the alveolar subtype of RMS (ARMS), which is a more aggressive tumor than the embryonal form (ERMS) that lacks PAX3-FKHR and is less likely to be metastatic or locally invasive (2–5). PAX3-FKHR can transform NIH3T3 cells and chicken embryo fibroblasts (6, 7), whereas experimentally induced expression of PAX3-FKHR in ERMS cells has been shown to result in more rapid tumor growth and local tissue invasion (8). PAX3-FKHR has recently been shown, when expressed in mouse Myf6 expressing developing myoblasts, to promote formation of tumors that histologically and immunohistochemically resemble human ARMS (9). PAX3-FKHR contains the NH2-terminal DNA binding domain of PAX3 fused in frame with the COOH-terminal transactivation do-