Research ArticleCancer

Antibody-mediated targeting of TNFR2 activates CD8+ T cells in mice and promotes antitumor immunity

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Science Translational Medicine  02 Oct 2019:
Vol. 11, Issue 512, eaax0720
DOI: 10.1126/scitranslmed.aax0720

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Tampering with TNFR2

Because tumor necrosis factor receptor 2 (TNFR2) is expressed on effector T cells as well as regulatory T cells, it is unclear whether TNFR2 activation could be exploited for cancer immunotherapy. Tam et al. screened a library of mouse anti-TNFR2 antibodies. One antibody, Y9, showed impressive antitumor activity in multiple implanted models without any toxicity. Efficacy was dependent on the Fc portion of the antibody and most likely mediated by effector T cells. Similar anti-human TNFR2 antibodies could provide costimulation to human cells in vitro and showed efficacy in humanized mouse models. These results suggest that certain TNFR2 antibodies could be developed for use in the clinic.

Abstract

Tumor necrosis factor receptor 2 (TNFR2) is the alternate receptor for TNF and can mediate both pro- and anti-inflammatory activities of T cells. Although TNFR2 has been linked to enhanced suppressive activity of regulatory T cells (Tregs) in autoimmune diseases, the viability of TNFR2 as a target for cancer immunotherapy has been underappreciated. Here, we show that new murine monoclonal anti-TNFR2 antibodies yield robust antitumor activity and durable protective memory in multiple mouse cancer cell line models. The antibodies mediate potent Fc-dependent T cell costimulation and do not result in significant depletion of Tregs. Corresponding human agonistic monoclonal anti-TNFR2 antibodies were identified and also had antitumor effects in humanized mouse models. Anti-TNFR2 antibodies could be developed as a novel treatment option for patients with cancer.

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