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

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-beta is highly expressed in the TCM and accumulates in the plasma. TGF-beta 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-beta blockade.

Automated summary

Monocytic myeloid-derived suppressor cells (M-MDSCs) are expanded in colorectal cancer (CRC) patients, inhibiting T cell proliferation. Blocking IL-10 released by HLA-DR- cells abrogates the suppressive function of M-MDSCs. Tumour conditioned media (TCM) reduces HLA-DR expression, increases IL-10 release, and promotes monocyte suppressive activity. TGF-beta in TCM drives monocyte immunosuppressivity and is enriched at the invasive margin of CRC.