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Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases

Cancer Gene Therapy volume 23, pages 188–198 (2016)Cite this article

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Abstract

Assumptions that liver immune cells and immunosuppressive pathways are similar to their counterparts in other spaces have led to gaps in our understanding of intrahepatic neoplasm aggressiveness. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of antitumor immunity and pose a major obstacle to solid tumor treatment. Liver MDSCs (L-MDSCs) associated with liver metastases (LM) are particularly problematic by contributing to intrahepatic immunosuppression that promotes tumor progression. L-MDSCs have been reported to expand in response to granulocyte-macrophages colony-stimulating factor (GM-CSF) and suppress antitumor immunity in LM. To extend these findings, we examined mechanisms of intrahepatic immunosuppression exploited by L-MDSCs. We found that the majority of L-MDSCs co-expressed GM-CSF receptor (GM-CSF-R), indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1), while demonstrating high levels of signal transducer and activator of transcription factor 3 (STAT3) activation. GM-CSF-secreting tumor cells induced STAT3 phosphorylation in L-MDSCs in addition to expression of IDO and PD-L1. GM-CSF or GM-CSF-R blockade markedly reduced L-MDSC IDO and PD-L1 expression, implicating tumor-derived GM-CSF in supporting L-MDSC-immunoinhibitory molecule expression. Small-molecule inhibitors of Janus-activated kinase 2 (JAK2) and STAT3 also dramatically diminished IDO and PD-L1 expression in L-MDSCs. We determined that STAT3 exerts transcriptional control over L-MDSC IDO and PD-L1 expression by binding to the IDO1 and PD-L1 promoters. Our data suggest that the GM-CSF/JAK2/STAT3 axis in L-MDSCs drives immunosuppression in a model of LM and blockade of this pathway may enable rescue of intrahepatic antitumor immunity.

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Acknowledgements

We thank Immunomedics, Inc. for generously providing the Wi2 anti-idiotype CAR antibody. We also 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. We are grateful for technical support from Gary Point. Support for this work was provided by the National Institutes of Health (1K08CA160662-01A1).

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Authors and Affiliations

  1. Division of Surgical Oncology, Department of Surgery, Roger Williams Medical Center, Providence, RI, USA

    M Thorn, P Guha, M Cunetta, N J Espat & S C Katz

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

    N J Espat & S C Katz

  3. Department of Surgery and Cell Biology, New York University School of Medicine, New York, NY, USA

    G Miller

  4. Department of Medicine, Tufts University School of Medicine, Boston, MA, USA

    R P Junghans

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Correspondence to S C Katz.

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Thorn, M., Guha, P., Cunetta, M. et al. Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases. Cancer Gene Ther 23, 188–198 (2016). https://doi.org/10.1038/cgt.2016.19

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