LXR/ApoE activation restricts innate immune suppression in cancer Journal Article
| Authors: | Tavazoie, M. F.; Pollack, I.; Tanqueco, R.; Ostendorf, B. N.; Reis, B. S.; Gonsalves, F. C.; Kurth, I.; Andreu-Agullo, C.; Derbyshire, M. L.; Posada, J.; Takeda, S.; Tafreshian, K. N.; Rowinsky, E.; Szarek, M.; Waltzman, R. J.; McMillan, E. A.; Zhao, C.; Mita, M.; Mita, A.; Chmielowski, B.; Postow, M. A.; Ribas, A.; Mucida, D.; Tavazoie, S. F. |
| Article Title: | LXR/ApoE activation restricts innate immune suppression in cancer |
| Abstract: | 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. Therapeutic agonism of the LXR/ApoE axis promotes anti-tumor immunity by targeting immunosuppressive innate immune cells. © 2018 Elsevier Inc. |
| Keywords: | signal transduction; adult; controlled study; protein expression; aged; human cell; major clinical study; clinical trial; nonhuman; protein function; animal cell; mouse; phenotype; animal tissue; cell survival; cancer immunotherapy; protein targeting; in vivo study; enzyme activation; in vitro study; cell population; cytotoxic t lymphocyte; innate immunity; informed consent; tumor growth; immunosuppressive treatment; t lymphocyte activation; tumor immunology; apolipoprotein e; tumor escape; myeloid; immune therapy; limit of quantitation; cancer; human; male; female; priority journal; article; liver x receptor; lxr; apoe; mdsc; myeloid-derived suppressor cell; lrp8; nuclear hormone receptor |
| Journal Title: | Cell |
| Volume: | 172 |
| Issue: | 4 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2018-02-08 |
| Start Page: | 825 |
| End Page: | 840.e18 |
| Language: | English |
| DOI: | 10.1016/j.cell.2017.12.026 |
| PROVIDER: | scopus |
| PUBMED: | 29336888 |
| PMCID: | PMC5846344 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
