Tuesday, August 18, 2015

IL-9 puts the brakes on tumor growth

TNF family receptors control the magnitude and functionality of immune response. Several of them have been targeted for therapeutic purpose (4-1BB, CD40L, BAFF-R). 

GITR (Glucocorticoid-Induced TNFR-related protein), a member of TNF superfamily, was initially implicated in inhibiting regulatory T cell (Tregs) function. However, work on this molecule receded into oblivion for these past few years due to overall failure of immunological research to develop Tregs based therapies.

Now, new study in Nature Medicine put forward novel mechanism of action for GITR. This study showed that GITR stimulation amplified IL-9 production from T helper cells and contributed to tumor protection.

First, the authors showed that GITR stimulating antibody inhibited tumor growth in a CD4-dependent manner.

Next, they showed that GITR stimulation improved tumor protection in an IL-4Rα-dependent manner.

This observation led to discovery that GITR stimulating antibody improved tumor protection via IL-9 production [that requires IL-4Rα signaling].

In vitro experiments showed that GITR stimulating antibody indeed promoted Th9 differentiation (Th2 cells showed minimal cancer protection). 

Finally, the authors showed that GITR stimulating antibody shifted the balance in favor of CD8 T cells in tumor environment.

These results suggest that GITR targeting could provide additional layer of protection against solid tumors. 

David Usharauli 

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