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Tavazoie, Masoud F.; Pollack, Ilana; Tanqueco, Raissa; Ostendorf, Benjamin N.; Reis, Bernardo S.; Gonsalves, Foster C.; Kurth, Isabel; Andreu-Agullo, Celia; Derbyshire, Mark L.; Posada, Jessica; Takeda, Shugaku; Tafreshian, Kimia N.; Rowinsky, Eric; Szarek, Michael; Waltzman, Roger J.; Mcmillan, Elizabeth A.; Zhao, Connie; Mita, Monica; Mita, Alain; Chmielowski, Bartosz; Postow, Michael A.; Ribas, Antoni; Mucida, Daniel; Tavazoie, Sohail F.
Cell, 02/2018, Volume: 172, Issue: 4Journal Article
Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)—an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients. Display omitted •LXR agonism reduces immunosuppressive MDSC levels in mice and cancer patients•LXR transcriptional target ApoE impairs MDSC survival•LXR-induced MDSC depletion enhances activation of cytotoxic T lymphocytes (CTLs)•CTL activation occurs in mice and patients, enhancing tumor immunotherapy in mice Therapeutic agonism of the LXR/ApoE axis promotes anti-tumor immunity by targeting immunosuppressive innate immune cells.
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