Research ArticleCancer Immunotherapy

Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs

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Sci. Signal.  17 Jan 2017:
Vol. 10, Issue 462, eaaf8608
DOI: 10.1126/scisignal.aaf8608

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Killing ovarian cancer by trapping TNFR2

Signaling by tumor necrosis factor (TNF) family promotes tumor growth and progression. The TNF receptor 2 (TNFR2) is present on the surface of immunosuppressive regulatory T cells and some tumor cells. Torrey et al. (see coverage by Chen and Oppenheim) developed antibodies that bind and lock TNFR2 in an inactive conformation. The antibodies killed ovarian cancer cells in culture. Additionally, the antibodies inhibited the proliferation of regulatory T cells while promoting the proliferation of effector T cells isolated from metastatic sites (ascites) in ovarian cancer patients. The antibodies had less of an effect on T cells isolated from the peripheral blood of normal donors. Thus, these antibodies may be more specific and less toxic than current TNFR antibodies, providing a new path for treating ovarian cancer.

Abstract

Major barriers to cancer therapy include the lack of selective inhibitors of regulatory T cells (Tregs) and the lack of broadly applicable ways to directly target tumors through frequently expressed surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is an attractive target protein because of its restricted abundance to highly immunosuppressive Tregs and oncogenic presence on human tumors. We characterized the effect of TNFR2 inhibition using antagonistic antibodies. In culture-based assays, we found that two TNFR2 antagonists inhibited Treg proliferation, reduced soluble TNFR2 secretion from normal cells, and enabled T effector cell expansion. The antagonistic activity occurred in the presence of added TNF, a natural TNFR2 agonist. These TNFR2 antibodies killed Tregs isolated from ovarian cancer ascites more potently than it killed Tregs from healthy donor samples, suggesting that these antibodies may have specificity for the tumor microenvironment. The TNFR2 antagonists also killed OVCAR3 ovarian cancer cells, which have abundant surface TNFR2. The antibodies stabilized antiparallel dimers in cell surface TNFR2 that rendered the receptor unable to activate the nuclear factor κB pathway and trigger cell proliferation. Our data suggest that, by targeting tumor cells and immunosuppressive tumor-associated Tregs, antagonistic TNFR2 antibodies may be an effective treatment for cancers positive for TNFR2.

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