Interleukin-17A Mediates Resistance to Anti-VEGF Therapy

Inhibitors of VEGF signaling have been developed as anticancer therapies, but as is the case with other targeted therapies, responses are limited by intrinsic or acquired drug resistance. Given that cancer cells co-opt the surrounding normal stroma to establish a tumor microenvironment permissive for angiogenesis, Chung and colleagues hypothesized that anti-VEGF therapy resistance is driven by tumor-secreted factors. A comparison of proteins secreted by VEGF antibody-sensitive and resistant tumor models revealed that the most abundant protein secreted by resistant cells was interleukin-17A (IL-17A), the canonical cytokine expressed by T_H17 lymphocytes. Mice bearing VEGF antibody-resistant tumors had high circulating levels of IL-17A as well as granulocyte colony-stimulating factor (G-CSF) and prokineticin 2 (PROK2), a proangiogenic factor induced by G-CSF. Use of an IL-17A neutralizing antibody or deletion of the IL-17 receptor significantly improved the antitumor activity of VEGF-specific antibodies, whereas forced expression of IL-17A conferred resistance to VEGF antibody-sensitive tumors, pointing to a key role of IL-17A in resistance to VEGF-directed therapy in the models examined and raising the possibility that inhibition of IL-17 signaling may potentiate the activity of VEGF-targeted antiangiogenic therapies. IL-17A expressed by tumor-infiltrating T_H17 cells after VEGF antibody treatment induced the mobilization and recruitment of immature myeloid cells to the tumor microenvironment and activated tumor-associated fibroblasts, suggesting that tumor-secreted IL-17A acts in a paracrine fashion. In syngeneic lung and colon cancer models, the IL-17A-induced recruitment of immature myeloid cells was associated with immunosuppression and expression of PROK2 within tumors. Advanced-stage human colorectal cancers also showed increased infiltration of T_H17 lymphocytes that was correlated with the number of PROK2-expressing neutrophils, suggesting that these findings may be clinically relevant and that the degree of T_H17 cell infiltration could potentially be used to predict response to anti-VEGF therapy.

Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, et al. An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 2013 Aug 4 [Epub ahead of print].