Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T

Cancer Immunol Immunother. 2015 Jul;64(7):817-29. doi: 10.1007/s00262-015-1692-6. Epub 2015 Apr 8.


Chimeric antigen receptor-modified T cell (CAR-T) technology, a promising immunotherapeutic tool, has not been applied specifically to treat liver metastases (LM). While CAR-T delivery to LM can be optimized by regional intrahepatic infusion, we propose that liver CD11b+Gr-1+ myeloid-derived suppressor cells (L-MDSC) will inhibit the efficacy of CAR-T in the intrahepatic space. We studied anti-CEA CAR-T in a murine model of CEA+ LM and identified mechanisms through which L-MDSC expand and inhibit CAR-T function. We established CEA+ LM in mice and studied purified L-MDSC and responses to treatment with intrahepatic anti-CEA CAR-T infusions. L-MDSC expanded threefold in response to LM, and their expansion was dependent on GM-CSF, which was produced by tumor cells. L-MDSC utilized PD-L1 to suppress anti-tumor responses through engagement of PD-1 on CAR-T. GM-CSF, in cooperation with STAT3, promoted L-MDSC PD-L1 expression. CAR-T efficacy was rescued when mice received CAR-T in combination with MDSC depletion, GM-CSF neutralization to prevent MDSC expansion, or PD-L1 blockade. As L-MDSC suppressed anti-CEA CAR-T, infusion of anti-CEA CAR-T in tandem with agents targeting L-MDSC is a rational strategy for future clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Carcinoembryonic Antigen / immunology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Granulocyte-Macrophage Colony-Stimulating Factor / biosynthesis
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Liver / cytology
  • Liver / pathology
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / secondary
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myeloid Cells / immunology*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Fusion Proteins / therapeutic use*
  • STAT3 Transcription Factor / metabolism
  • Tumor Burden


  • B7-H1 Antigen
  • Carcinoembryonic Antigen
  • Cd274 protein, mouse
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Granulocyte-Macrophage Colony-Stimulating Factor