Circulating myeloid‐derived suppressor cells: An independent prognostic factor in patients with breast cancer

Abstract

Evading immune destruction is a hallmark of cancer. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid immune cells, are thought to foster the establishment of an immunosuppressive tumor microenvironment, but it remains unclear how. This study aims to determine the levels of circulating MDSCs and their subpopulations and test their immunosuppressive functions in patients with breast cancer (BC). We analyzed the fractions of MDSCs in freshly isolated peripheral blood mononuclear cells of patients with BC and healthy donors using flow cytometry. Circulating MDSCs were further phenotyped using fluorescently labeled antihuman monoclonal antibodies. Coculture experiments revealed the effects of MDSCs on CD3 + T cell response. Moreover, we correlated circulating MDSC levels with clinicopathological features of patients with BC. We show that the fraction of HLA-DR -CD33 + MDSCs in peripheral blood is about 10-fold higher in patients with BC than in healthy control individuals. The levels of all MDSC subpopulations, including monocytic and granulocytic MDSCs, are significantly elevated. Coculture experiments of purified HLA-DR -CD33 + MDSCs and CD3 + T cells demonstrate that T cell proliferation is more effectively inhibited by BC patient-derived MDSCs than by healthy control MDSCs. Moreover, increased circulating MDSC levels robustly associate with advanced BC stage and positive lymph node status. By being more abundant and more effective T cell suppressors, BC patientderived circulating MDSCs exert a dual immunosuppressive effect. Our findings pave the way to develop novel diagnostic and immunotherapeutic strategies, aimed at detecting and inhibiting MDSCs in patients with BC.

The New Era of Cancer Immunotherapy: Targeting Myeloid-Derived Suppressor Cells to Overcome Immune Evasion

“…Additionally, Bergenfelz et al (92), reported an expansion of circulating CD14 + HLA-DR −/low M-MDSCs in patients with locoregional recurrence or metastatic BC, which was correlated with increased metastasis to lymph nodes and visceral organs, suggesting that circulating M-MDSCs could be a potential biomarker for disease progression and a guide to individualize efficient immunomodulatory treatments. Also Safarzadeh et al (105) showed that M-MDSCs (HLA-DR − CD33 + CD14 + ) represent a high percentage compared with the G-MDSCs (HLA-DR − CD33 + CD15 + ) subpopulation in BC patients. A recent study found that cells with the M-MDSCs phenotype CD14 + HLA-DR −/low are present at significantly higher frequencies in early-stage BC patients (40 patients with clinical stages I/II), suggesting that M-MDSCs mostly participate to the development of BC by protecting tumor cells from immune attack.…”

The Immune Microenvironment of Breast Cancer Progression

“…High levels of MDSCs have been identified as a poor prognostic marker for many cancers, and most likely participate in the pro-tumourigenic pathway through the suppression and inhibition of the host anti-tumour immune response [55,56]. BCa patients have higher circulating MDSC counts than their normal-matched counterparts [57]. Greater quantities of MDSCs isolated from the blood of these patients correlated with poor prognosis, and when cultured with T cells in vitro they were able to significantly inhibit proliferation of the lymphocytic population in comparison to MDSCs derived from normal subjects [57].…”

Oral Capecitabine-Vinorelbine Is Associated with Longer Overall Survival When Compared to Single-Agent Capecitabine in Patients with Hormone Receptor-Positive Advanced Breast Cancer

“…Of note, patients receiving CV had significantly lower NLR after one treatment cycle when compared to patients treated with C. These findings indicate a potential immunoregulatory effect of the CV combination and suggest that CV-induced immune system modulation may at least in part explain the observed association with longer patient survival. Prospective studies are needed to confirm and consolidate these data, as well as to explore the effect of C and CV on specific subpopulations of myeloid-derived suppressor cells (MDSCs) that are associated with worse mBC patient prognosis [31,32], or on antitumor lymphocytic effectors associated with higher treatment efficacy [33].…”