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

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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.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

BM:

Bone marrow

CAR-T:

Chimeric antigen receptor-modified T cells

CEA:

Carcinoembryonic antigen

CLL:

Chronic lymphocytic leukemia

FMO:

Fluorescence minus one

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

IDO:

Indolamine 2,3-dioxygenase

IFNγ:

Interferon gamma

IL2:

Interleukin 2

iNOS:

Inducible nitric oxide synthase

LM:

Liver metastases

L-MDSC:

Liver myeloid-derived suppressor cells

NO:

Nitric oxide

NPC:

Non-parenchymal cells

PD-1:

Programmed death 1

PD-L1:

Programmed death ligand 1

pSTAT3:

Phosphorylated signal transducer and activator of transcription 3

SSG:

Sodium stibogluconate

STAT3:

Signal transducer and activator of transcription 3

UT:

Unmodified/untransduced T cells

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Acknowledgments

The authors would like to thank Erica Santos for her technical assistance, Dr. Jeffrey Schlom for providing MC38 and MC38CEA cell lines, Dr. Tasuku Honjo for providing the PD-1−/− mice to begin our in-house breeding, and Dr. Hansen for generously providing the Wi2 anti-idiotype CAR antibody. We would like to thank Dr. John Morgan and Roger Williams Medical Center Core Facility for providing us with the necessary equipment to carry out flow cytometry and in vivo bioluminescence experiments. Support for this work was provided by the National Institutes of Health (1K08CA160662-01A1), the Society of Surgical Oncology Clinical Investigator Award supported by an education grant from Genentech, and the Rhode Island Foundation.

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The authors have no conflict of interest to disclose.

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    Authors and Affiliations

    1. Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, 825 Chalkstone Avenue, Prior 4, Providence, RI, 02908, USA

      Rachel A. Burga, Mitchell Thorn, Gary R. Point, Prajna Guha, Cang T. Nguyen, Lauren A. Licata, N. Joseph Espat & Steven C. Katz

    2. Boston University School of Medicine, Boston, MA, USA

      Rachel A. Burga, Mitchell Thorn, Gary R. Point, Prajna Guha, Cang T. Nguyen, Lauren A. Licata, N. Joseph Espat & Steven C. Katz

    3. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

      Ronald P. DeMatteo

    4. Department of Surgery and Immunology Laboratory, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA

      Alfred Ayala

    5. Department of Medicine, Roger Williams Medical Center, Providence, RI, USA

      Richard P. Junghans

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    1. Rachel A. Burga
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    Rachel A. Burga and Mitchell Thorn have contributed equally to this work.

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    Burga, R.A., Thorn, M., Point, G.R. et al. 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 64, 817–829 (2015). https://doi.org/10.1007/s00262-015-1692-6

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