Circulating and Tumor-Infiltrating Myeloid-Derived Suppressor Cells in Patients with Colorectal Carcinoma

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of myeloid cells that suppress T cell immunity in tumor-bearing hosts. In patients with colon cancer, MDSCs have recently been described as Lin−/lowHLA-DR−CD11b+CD33+ cells correlating with cancer stage, metastasis and chemotherapy response. To learn in more detail the dynamic change and clinical relevance of circulating and tumor-infiltrating Lin−/lowHLA-DR−CD11b+CD33+ MDSC in colorectal cancer, we harvested the blood from 64 patients with varying stage of colorectal cancer and tumor and matched paraneoplastic tissues from 5 patients with advanced colorectal cancer, subjected them to multicolor flow cytometric analysis of percentage, absolute number and phenotype of MDSC and finally characterized their immunosuppressive functions. Our results demonstrate that peripheral blood from colorectal cancer patients contains markedly increased percentage and absolute number of Lin−/lowHLA-DR−CD11b+CD33+ MDSCs compared with healthy individuals, and this increase is closely correlated with clinical cancer stage and tumor metastasis but not primary tumor size and serum concentrations of cancer biomarker. A similar increase of MDSCs was also observed in the tumor tissues. Phenotyping MDSCs shows that they express high CD13 and CD39, low CD115, CD117, CD124 and PD-L1, and devoid of CD14, CD15 and CD66b, reminiscent of precursor myeloid cells. MDSCs from cancer patients but not healthy donors have the immunosuppressive activity and were able to inhibit in vitro autologous T-cell proliferation. Collectively, this study substantiates the presence of increased immunosuppressive circulating and tumor-resident Lin−/lowHLA-DR−CD11b+CD33+ MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis, and suggests that pharmacologic blockade of MDSCs should be considered in future clinical trials.

Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

“…Although previous studies have reported higher levels of circulating T reg and/or MDSCs in advanced (Stage III/IV) BC 29 and other solid tumors, 30 in this study, early-stage (Stage I/II) IBC patients appear to have comparable immunosuppressive profiles to HDs. The dramatic decline in anti-HER2 Th1 responses in these patients, therefore, is even more compelling.…”

Identification of CD4+CD25+CD127− regulatory T cells and CD14+HLA−DR−/low myeloid-derived suppressor cells and their roles in the prognosis of breast cancer

“…suppressing tumor-specific immunity (24). A recent study revealed that the percentages of CD4 + CD25 T cells was higher in the peripheral blood mononuclear cells in patients with gastric and esophageal cancer compared to that of the normal individuals (25).…”

Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells

“…7 In several other studies, including breast cancer, gastric cancer, melanoma, pancreatic and esophageal cancer, it has been shown that the frequencies of circulating MDSCs correlate with disease stage and metastasis and that the increase in the number of these MDSCs is an independent prognostic factor and could predict response to therapy. [57][58][59] Moreover, patients with stage IV solid tumors had the highest percentage of MDSCs. When they divided these stage IV patients into those with limited and those with extensive (defined as a diffuse involvement of one organ system or three or more distinct organ sites involved) metastatic tumor burden, the latter had both higher mean percentages and higher absolute numbers of circulating MDSCs.…”