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
  • 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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