TGF-β orchestrates the phenotype and function of monocytic myeloid-derived suppressor cells in colorectal cancer.

Autor: Gneo L; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B152TT, UK., Rizkalla N; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B152TT, UK., Hejmadi R; Department of Pathology, University Hospital Birmingham, Birmingham, UK., Mussai F; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B152TT, UK., de Santo C; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B152TT, UK., Middleton G; Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham, B152TT, UK. G.Middleton@bham.ac.uk.
Jazyk: angličtina
Zdroj: Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2022 Jul; Vol. 71 (7), pp. 1583-1596. Date of Electronic Publication: 2021 Nov 02.
DOI: 10.1007/s00262-021-03081-5
Abstrakt: 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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