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Monocytic and granulocytic myeloid-derived suppressor cell plasticity and differentiation are organ-specific

Oncogene volume 40, pages 693–704 (2021)Cite this article

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Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that proliferate in the setting of cancer and have potent immunosuppressive functions hindering anti-tumor immunity. Here we establish that the immunologic landscape and tumor microenvironments (TME) vary between different organs which discretely shape MDSC repertoires. We found that pSTAT3 signaling exerts a dominant effect on MDSC programming in liver metastasis (LM). In contrast, in lung metastasis (LuM), MDSC programming is driven mainly by pSTAT5. Adoptive transfer of LM-MDSC into LuM resulted in a shift from pSTAT3 signaling to pSTAT5, in association with an overall shift toward lung MDSC programming. A shift from more immunosuppressive M-MDSC to G-MDSC, along with enhanced differentiation of MDSCs into pro-inflammatory M1 macrophages in LuM, indicated that MDSC plasticity and differentiation patterns are environmentally dependent. Using mass spectroscopy, we confirmed that LM-MDSCs showed enhanced expression of key proliferation pathway markers. This confirmed that liver-specific MDSC programing was comprehensive but reversible, implying that therapeutic targeting of LM-MDSC could prime the TME in a favorable manner. Our data suggest that MDSC programming in response to malignancy is highly dependent on organ-specific conditions and is modifiable.

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Fig. 1: Accumulation of immunosuppressive M-MDSC in tumor-bearing liver as compared to tumor-bearing lungs.
Fig. 2: LM-MDSC and LuM-MDSC proliferation occurs via pSTAT3 and pSTAT5 signaling pathways, respectively.
Fig. 3: Uniform myeloid cell subset within tumors is organ and not cell type-dependent.
Fig. 4: Shift from M-MDSC to G-MDSC phenotype in LuM and normal lung with subsequent shift in STAT signaling.
Fig. 5: Distinct genetic and proteomic profile of LM-MDSC and LuM MDSC.

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Acknowledgements

We would like to thank Dr. Louis Chai and Dr. Chandra C. Ghosh for proofreading and technical assistance. We would also like to acknowledge Dr. Benjamin Barlock for SWATH-MS technical assistance and Dr. Fatemeh Akhlaghi for access to the Mass Spectrometer.

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Authors and Affiliations

  1. Roger Williams Medical Center, Immuno-oncology Institute and Department of Medicine Immunotherapy Service, Providence, RI, USA

    Prajna Guha, Jillian Gardell, Benjamin Rabinowitz, Mikayla Lopes & Steven C. Katz

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

    Prajna Guha & Steven C. Katz

  3. Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, USA

    Prajna Guha, Nicholas A. DaSilva, David Rowley & Steven C. Katz

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  1. Prajna Guha
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Guha, P., Gardell, J., Rabinowitz, B. et al. Monocytic and granulocytic myeloid-derived suppressor cell plasticity and differentiation are organ-specific. Oncogene 40, 693–704 (2021). https://doi.org/10.1038/s41388-020-01559-7

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