TGF-β orchestrates the phenotype and function of monocytic myeloid-derived suppressor cells in colorectal cancer
- PMID: 34727230
- PMCID: PMC9188538
- DOI: 10.1007/s00262-021-03081-5
TGF-β orchestrates the phenotype and function of monocytic myeloid-derived suppressor cells in colorectal cancer
Abstract
Background: Monocytic myeloid-derived suppressor cells (M-MDSCs) are significantly expanded in the blood of colorectal cancer (CRC) patients. However, their presence and underlying mechanisms in the tumour microenvironment of CRC have not been examined in detail.
Methods: Tumour tissues and peripheral blood from CRC patients were analysed for the presence of M-MDSCs. The mechanisms of suppression were analysed by blocking pathways by which MDSCs abrogate T cell proliferation. Co-culture of CRC cells with monocytes were performed with and without cytokine blocking antibodies to determine the mechanism by which CRC cells polarise monocytes. Multi-spectral IHC was used to demonstrate the intra-tumoral location of M-MDSCs.
Results: Tumour tissues and blood of CRC patients contain M-MDSCs which inhibit T cell proliferation. Whilst inhibition of arginase and nitric oxide synthase 2 fail to rescue T cell proliferation, blockade of IL-10 released by these HLA-DR- cells abrogates the suppresivity of M-MDSCs. Tumour conditioned media (TCM) significantly reduces HLA-DR expression, increases IL-10 release from monocytes and causes them to become suppressive. TGF-β is highly expressed in the TCM and accumulates in the plasma. TGF-β reduces HLA-DR expression and drives monocyte immunosuppressivity. The invasive margin of CRC is enriched in CD14+ HLA-DR- cells in close proximity to T cells.
Conclusions: Our study demonstrates the cross-talk between CRC cells, M-MDSCs and T cells. Characterisation of CRC M-MDSCs point to therapeutic avenues to target these cells in addition to TGF-β blockade.
Keywords: Colorectal cancer; IL-10; M-MDSCs; TGFβ; pSTAT3.
© 2021. The Author(s).
Conflict of interest statement
The authors have no disclosures and no competing interests in relation to this manuscript or work.
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References
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- Duffy A, Zhao F, Haile L, Gamrekelashvili J, Fioravanti S, Ma C, et al. Comparative analysis of monocytic and granulocytic myeloid-derived suppressor cell subsets in patients with gastrointestinal malignancies. Cancer Immunol Immunother. 2013;62(2):299–307. doi: 10.1007/s00262-012-1332-3. - DOI - PMC - PubMed
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