In cancer, tumors may skew a cytokine tug-of-war to favor their own growth and survival, according to Wang et al. on page 1457.
The signature Th1 cytokine IFN-γ is a well-known tumor antagonist that promotes tumor attack by killer T cells and renders tumor cells more susceptible to death. IFN-γ also suppresses the development of IL-17–producing Th17 cells, which have recently been suspected to aid tumors. Here, the authors find that IL-17 helps tumors grow both by inhibiting Th1 differentiation and activating the oncogenic signaling molecule STAT3.
In mice that lack IL-17, two types of established tumors (melanoma and bladder) grew slowly. Without IL-17, IFN-γ–producing T cells flooded the tumor and stunted its growth. When IFN-γ was missing, Th17 cells won out, allowing tumor growth to skyrocket.
IL-17 activated STAT3 indirectly via the cytokine IL-6. And because IL-6 also promotes Th17 differentiation, the tumor-promoting cycle was amplified. STAT3 drove the expression of target genes that promote cell survival, proliferation, and angiogenesis. In this way, tumor growth was also attenuated by blocking IL-6 signals.
Both tumor cells and surrounding endothelial cells responded to IL-6, but the endothelial cells had more activated STAT3. Senior author Drew Pardoll points out that the contribution of cells around the tumor may vary among cancers. Some tumors, for example, could be surrounded by cells bearing fewer IL-6 receptors than those studied here. “It's an elegant notion that the Th1 pathway produces anti-cancer immunity and the Th17 pathway promotes cancer,” says Pardoll. “I'd be pleasantly surprised if in the end it really is that simple.”