title: Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T.
abstract: 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.
authors: Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, 825 Chalkstone Avenue, Prior 4, Providence, RI, 02908, USA.
authors: Rachel A
authors: RA
authors: Burga
authors: Mitchell
authors: M
authors: Thorn
authors: Gary R
authors: GR
authors: Point
authors: Prajna
authors: P
authors: Guha
authors: Cang T
authors: CT
authors: Nguyen
authors: Lauren A
authors: LA
authors: Licata
authors: Ronald P
authors: RP
authors: DeMatteo
authors: Alfred
authors: A
authors: Ayala
authors: N
authors: N
authors: Joseph Espat
authors: Richard P
authors: RP
authors: Junghans
authors: Steven C
authors: SC
authors: Katz
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology* / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden
chemical_list: D060890:B7-H1 Antigen; D002272:Carcinoembryonic Antigen; C498919:Cd274 protein, mouse; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor