2. Academic Validation
  3. LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

LXR/ApoE Activation Restricts Innate Immune Suppression in Cancer

  • Cell. 2018 Feb 8;172(4):825-840.e18. doi: 10.1016/j.cell.2017.12.026.
Masoud F Tavazoie 1,  Ilana Pollack 2,  Raissa Tanqueco 2,  Benjamin N Ostendorf 2,  Bernardo S Reis 3,  Foster C Gonsalves 4,  Isabel Kurth 4,  Celia Andreu-Agullo 4,  Mark L Derbyshire 2,  Jessica Posada 2,  Shugaku Takeda 4,  Kimia N Tafreshian 2,  Eric Rowinsky 4,  Michael Szarek 5,  Roger J Waltzman 4,  Elizabeth A Mcmillan 2,  Connie Zhao 2,  Monica Mita 6,  Alain Mita 6,  Bartosz Chmielowski 7,  Michael A Postow 8,  Antoni Ribas 7,  Daniel Mucida 9,  Sohail F Tavazoie 10
Affiliations

Affiliations

  • 1 Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA. Electronic address: [email protected].
  • 2 Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.
  • 3 Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA.
  • 4 Rgenix, New York, NY, USA.
  • 5 Rgenix, New York, NY, USA; School of Public Health, Downstate Medical Center, Brooklyn, NY, USA.
  • 6 Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 7 Department of Medicine, University of California, Los Angeles, CA, USA.
  • 8 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
  • 9 Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY, USA. Electronic address: [email protected].
  • 10 Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA. Electronic address: [email protected].
PMID: 29336888 DOI: 10.1016/j.cell.2017.12.026
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.

Keywords

ApoE; LRP8; LXR; MDSC; cancer; clinical trial; immune therapy; myeloid; nuclear hormone receptor; tumor immunology.

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