LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

被引：384

作者：

Tavazoie, Masoud F. ^{[1
,3
]}

Pollack, Ilana ^{[1
]}

Tanqueco, Raissa ^{[1
]}

Ostendorf, Benjamin N. ^{[1
]}

Reis, Bernardo S. ^{[2
]}

Gonsalves, Foster C. ^{[3
]}

Kurth, Isabel ^{[3
]}

Andreu-Agullo, Celia ^{[3
]}

Derbyshire, Mark L. ^{[1
]}

Posada, Jessica ^{[1
]}

Takeda, Shugaku ^{[3
]}

Tafreshian, Kimia N. ^{[1
]}

Rowinsky, Eric ^{[3
]}

Szarek, Michael ^{[3
,8
]}

Waltzman, Roger J. ^{[3
]}

Mcmillan, Elizabeth A. ^{[1
]}

Zhao, Connie ^{[1
]}

Mita, Monica ^{[4
]}

Mita, Alain ^{[4
]}

Chmielowski, Bartosz ^{[5
]}

Postow, Michael A. ^{[6
,7
]}

Ribas, Antoni ^{[5
]}

Mucida, Daniel ^{[2
]}

Tavazoie, Sohail F. ^{[1
]}

机构：

[1] Rockefeller Univ, Lab Syst Canc Biol, 1230 York Ave, New York, NY 10021 USA

[2] Rockefeller Univ, Lab Mucosal Immunol, 1230 York Ave, New York, NY 10021 USA

[3] Rgenix, New York, NY 10065 USA

[4] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA

[5] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

[7] Weill Cornell Med Coll, New York, NY USA

[8] Downstate Med Ctr, Sch Publ Hlth, Brooklyn, NY USA

来源：

CELL | 2018年 / 172卷 / 04期

关键词：

LIVER X RECEPTORS; T-CELLS; MYELOID CELLS; METASTATIC MELANOMA; REGULATORY T; PD-1; LXR; CHOLESTEROL; MECHANISMS; CTLA-4;

D O I：

10.1016/j.cell.2017.12.026

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：825 / +

页数：34

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