Editors' ChoiceCancer

Combining Anti-Inflammatory and Anti-Angiogenic Therapy

Science Signaling  24 Sep 2013:
Vol. 6, Issue 294, pp. ec224
DOI: 10.1126/scisignal.2004747

To meet the demand for oxygen and nutrients, growing tumors induce the growth of new blood vessels in a process called angiogenesis. Antibodies directed against vascular endothelial growth factor (VEGF), which promotes angiogenesis, have been developed as a therapeutic strategy to limit tumor growth. However, tumors often become refractory to antibodies against VEGF treatment (see Maniati and Hagemann). Chung et al. screened the factors secreted by cancer cell lines that are insensitive to antibodies against VEGF (EL4 cells) or sensitive to antibodies against VEGF (Tib-6 cells). EL4 cells secreted high concentrations of interleukin-17A (IL-17A), at a concentration ~10,000 times that released by Tib-6 cells, the greatest differential of the secreted factors measured. IL-17 triggers the release of proinflammatory cytokines. Compared with mice without tumors, mice with tumors formed from EL4 cells had higher circulating amounts of G-CSF (granulocyte colony-stimulating factor) and IL-6, both proinflammatory cytokines, and of the G-CSF–inducible factor Bv8, which promotes angiogenesis. These increases were ablated by injection of a neutralizing antibody directed against IL-17A. Growth of tumors formed from EL4 cells or the colon carcinoma cell line CT-26 was decreased in mice treated with antibodies against both VEGF and IL-17A compared with the growth of tumors in mice receiving antibodies against VEGF alone. Growth of EL4 tumors was also less in mice that were deficient in one of the subunits for the IL-17 receptor (Il17rc–/–) compared with that in wild-type mice. Furthermore, the growth of tumors formed from Tib-6 cells was increased if the cells were engineered to express IL-17A. Although the concentration of circulating IL-17A was similar in wild-type or Il17rc–/– mice with tumors formed from EL4 cells, the concentrations of circulating G-CSF and IL-6 were greater in wild-type mice than in Il17rc–/– mice. G-CSF recruits immature myeloid cells that are positive for CD11band Gr1; these cells suppress T cells and promote tumor angiogenesis and thereby enhance tumor progression. Wild-type mice had higher numbers of circulating and tumor-infiltrating CD11b+Gr1+ cells compared with Il17rc–/– mice or mice deficient in the G-CSF receptor, and CD11b+Gr1+ cells from Il17rc–/– mice showed reduced ability to suppress T cell function. Tumor-associated fibroblasts from wild-type, but not Il17rc–/–, mice produced proinflammatory cytokines in response to stimulation with IL-17A or the related IL-17F. T helper 17 (TH17) cells promote inflammation, and tumor infiltration by TH17 cells is associated with poor prognosis. The number of infiltrating TH17 cells was decreased in Lewis lung carcinomas in Il17rc–/– mice compared with those in wild-type mice. These results suggest that combining an antibody against IL-17 may attenuate tumor resistance to anti-angiogenic therapies.

A. S. Chung, X. Wu, G. Zhuang, H. Ngu, I. Kasman, J. Zhang, J.-M. Vernes, Z. Jiang, Y. G. Meng, F. V. Peale, W. Ouyang, N. Ferrara, An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat. Med. 19, 1114–1123 (2013).[PubMed]

E. Maniati, T. Hagemann, IL-17 mediates resistance to anti-VEGF therapy. Nat. Med. 19, 1092–1094 (2013).[PubMed]