Editors' ChoiceDRUG RESISTANCE

Co-opting a Tumor Predator to Provide Life Support

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Science Translational Medicine  11 Sep 2013:
Vol. 5, Issue 202, pp. 202ec149
DOI: 10.1126/scitranslmed.3007484

Tumor cells not only circumvent the intrinsic cellular mechanisms that prevent rogue proliferation, they also co-opt innocent bystander cells to support their malignant agenda. In particular, tumor cells must evade immunosurveillance and recruit cells in the tumor microenvironment to promote angiogenesis, in which new blood vessels are created to feed the tumor. Indeed, modulators of immunosurveillance and angiogenesis have both been demonstrated to be effective anticancer therapeutic strategies. However, as with most cancer treatments, tumors develop resistance to these therapies over time.

Chung et al. have discovered a paracrine signaling network through which immune cells promote resistance to anti-angiogenic therapy. The examined tumors not only escape attack by the immune system but actively co-opt immune cells to overcome pharmacological inhibition of angiogenesis. The authors first observed that interleukin-17 (IL-17)—the canonical cytokine of the tumor-infiltrating T helper type 17 (TH17) cells—was the most abundantly secreted protein in the conditioned medium of EL4 cells, a mouse lymphoma cell line that is resistant to therapies targeting the key angiogenic signaling protein, vascular endothelial growth factor (VEGF). IL-17 was secreted at much lower abundance in cells sensitive to anti-VEGF treatment. The authors then demonstrated that depletion of IL-17 either in vitro or in a mouse model enhanced sensitivity to anti-VEGF treatment, whereas stable expression of IL-17 rendered mouse models more resistant to anti-VEGF treatment. Moreover, treatment of wild-type mice and mice in which IL-17 was knocked out with anti-VEGF antibodies demonstrated that IL-17 signaling is required for the mobilization and tumor infiltration of immature myeloid cells known to drive tumor progression through immunosuppression and tumor angiogenesis.

Tumor cells use a remarkably creative and diverse array of molecular tricks to not only escape cell-intrinsic and -extrinsic antitumor safeguards but also to recruit other cells to actively support malignancy. Chung et al. illustrate an example in which tumor cells not only evade immunosurvellience but actively recruit immune cells to promote angiogenesis in the presence of VEGF inhibition. These results suggest that targeting immunosurveiliance may be used to overcome resistance to anti-angiogenic therapies.

A. S. Chung et al., An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat. Med. 19, 1114–1123 (2013). [Abstract]

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