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Immunol Cell Biol. 2014 Jul;92(6):475-80. doi: 10.1038/icb.2014.26. Epub 2014 Apr 15.

OX40 engagement depletes intratumoral Tregs via activating FcγRs, leading to antitumor efficacy.

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Department of Oncology, Novartis Institute for Biomedical Research, Cambridge, MA, USA.
Department of Laboratory Animal Services, Novartis Institute for Biomedical Research, Cambridge, MA, USA.
Novartis Biologics Center, Novartis Institute for Biomedical Research, Cambridge, MA, USA.
1] Department of Medical Oncology, Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, MA, USA [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.


Antibodies targeting checkpoint inhibitors or co-stimulatory receptors on T cells have shown significant antitumor efficacy in preclinical and clinical studies. In mouse tumor models, engagement of activating Fcγ receptor (FcγR)-expressing immune cells was recently shown to be required for the tumoricidal activity of antibodies recognizing the tumor necrosis factor superfamily receptor (TNFR) GITR (CD357) and CTLA-4 (CD152). In particular, activating FcγRs facilitated the selective elimination of intratumoral T-cell populations. However, it remains unclear whether FcγRs contribute to the antitumor efficacy of other immunomodulatory antibodies. Here, we explored the mechanism of antitumor activity mediated by an agonistic antibody (clone OX86) to the co-stimulatory TNFR OX40 (CD134). OX40 was highly expressed by intratumoral T cells, particularly those of the FoxP3(+) regulatory T-cell (Treg) lineage. OX86 administration resulted in the depletion of intratumoral regulatory T cells in an activating FcγR-dependent manner, which correlated with tumor regression. Together with previous data from our group and others, these findings support a mechanism whereby antibodies targeting antigens highly expressed by intratumoral T cells can mediate their elimination by FcγR-expressing immune cells, and facilitate subsequent antitumor immunity.

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