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

• Published in: Oncogene 2021-01, Vol.40 (3), p.693-704
• Main Authors: Guha, Prajna, Gardell, Jillian, Rabinowitz, Benjamin, Lopes, Mikayla, DaSilva, Nicholas A., Rowley, David, Katz, Steven C.
• Format: Article
• Language: English
• Subjects: 101/58; 13/31; 13/51; 13/95; 14/19; 38/77; 38/91; 631/67/322; 631/80/86; Adoptive transfer; Animals; Apoptosis; Bone marrow cells; Cancer; Cell Biology; Cell differentiation; Cell Line, Tumor; Cellular signal transduction; Development and progression; Granulocytes - metabolism; Granulocytes - pathology; Health aspects; Human Genetics; Immune response; Inflammation; Internal Medicine; Liver; Liver cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Macrophages; Male; Malignancy; Mass spectroscopy; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Microenvironments; Monocytes; Monocytes - metabolism; Monocytes - pathology; Myeloid cells; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Oncology; Oncology, Experimental; Organ Specificity; Physiological aspects; Plasticity; Suppressor cells; Therapeutic targets; Tumor Microenvironment
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01559-7

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.