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An IL-17-mediated paracrine network promotes tumor resistance to antiangiogenic therapy.

Boutouyrie-Dumont, Bruno (2014) An IL-17-mediated paracrine network promotes tumor resistance to antiangiogenic therapy. Biomarkers in Medicine, 8 (1). pp. 73-75. ISSN 1752-0363


Summary and comments ("Research Highlights" in News and Views of the journal "Biomarkers in Medicine") on :
An interleukin-17–mediated paracrine network promotes tumor resistance to anti-angiogenic therapy
Alicia S Chung, et al.
Nature medicine, Vol 19, 2013, 1114-1123

”A newly identified mechanism of resistance to anti-angiogenic therapy”
Anti-angiogenic therapy has improved cancer treatment successes but still there are cases of resistance to this therapy. Understanding inherent or acquired resistance mechanism(s) to therapy is always an important step in the search for new treatments. Drug resistance can come from the tumor itself (and typically takes time) or can come from the environment of the tumor e.g. fibroblasts, immune cells or extracellular matrix (and appears more rapidly). This article displays the series of experiments describing a fascinating mechanism, involving TH17 cells and IL-17, which may probably lead to treatment improvement.

To try to understand the mechanism, the authors used 2 cell lines, one resistant (EL4) and the other sensitive (Tib-6) to anti-angiogenic therapy. They assayed a series of potential “perpetrating” secreted mediators. The most important one was IL-17, known to be secreted by TH17 cells. IL-17 can then influence the production of other proinflammatory factors such as G-CSF, IL-6, Bv8.

In another series of experiments of implanting EL4 tumors in mice, they showed that anti-IL17 antibodies can improve the response to anti-angiogenic treatment. As EL4 cells have no IL-17 receptors, they also concluded the effect may come from a paracrine (and not autocrine) function.

Furthermore the authors demonstrated that the increase of IL-17 induced the increase of G-CSF. This increase of G-CSF induced the mobilization and recruitment of immature myeloid cells (CD11b+Gr1+ cells) in the tumor microenvironment.

Those cells were also shown to be functionally modulated by IL-17.

Secreted proteins were shown to come mainly from the stroma (and not from the tumor). The responsible cells were identified as the tumor-associated fibroblasts (TAFs). Data are shown that IL-17 can induce TAFs to produce proinflammatory cytokines such as G-CSF through MAPK and NF-κB signalling.

IL-17 is produced by TH17 cells. The authors compared the Lewis lung carcinoma tumor burden between mice having or not IL-17 receptors (IL-17RC KO). The burden was decreased in the IL-17RC KO mice. Likewise, concomitant treatment by an anti-IL17 antibody improved the effect of the anti-angiogenic treatment in a lung orthotopic model in wild type mice.

The data in this paper shows how adaptive immunity could be involved in the resistance to anti-angiogenic therapy. It also shows that IL-17 is not only responsible for cell recruitment but also can influence stroma cell functions.
The tumor types are also to be kept in mind. The data above are applicable to lung and colon cancer where it is known that TH17 cell presence in tumor correlate with bad prognosis. Different interpretation is to be made in the cases of ovarian and gastric cancers.
These data would support to give special attention to TH17 cell presence in tumor biopsies depending on the tumor types : another step towards personalized health care to improve the treatment of cancer patients.

Item Type: Article
Keywords: biomarker, interleukin 17, tumor resistance
Date Deposited: 13 Oct 2015 13:12
Last Modified: 13 Oct 2015 13:12


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