PAX3-FKHR induction (top) turns on STAT3 and helps tumors to hide.

Now, this group finds that expression of PAX3-FKHR also significantly dampens immune activation, in part by reducing surface levels of class I MHC on transfected cells. A microarray screen revealed that expression of the fusion protein repressed numerous genes, 40% of which are known targets of STAT1 and/or STAT3, including class I MHC and the cytokine IL-10. Recent studies have shown that overactive STAT3 contributes to tumor immune evasion by stifling inflammation and preventing crosstalk between innate and adaptive immune systems.

STAT3 also acts as a transcriptional coactivator with FKHR. The group now show that PAX3-FKHR also binds to STAT3, but not to STATs 2,4, and 6. Media from cells expressing the fusion protein contained at least one inhibitory cytokine, IL-10, and prevented dendritic cell (DC) activation. Mouse xenografts expressing PAX3-FKHR had decreased inflammatory responses because the numbers of both activated DCs and infiltrating neutrophils and macrophages were reduced.

This inhibition of DC activation and immune cell recruitment might help the tumor establish an immunoinhibitory environment in which to hide. Determining which target genes help the PAX3-FKHRSTAT3 complex to create this environment will require further experiments.