Myeloid cells in circulation and tumor microenvironment of breast cancer patients

Abstract

Pathological conditions including cancers lead to accumulation of a morphological mixture of highly immunosuppressive cells termed as myeloid-derived suppressor cells (MDSC). The lack of conclusive markers to identify human MDSC, due to their heterogeneous nature and close phenotypical and functional proximity with other cell subsets, made it challenging to identify these cells. Nevertheless, expansion of MDSC has been reported in periphery and tumor microenvironment of various cancers. The majority of studies on breast cancers were performed on murine models and hence limited literature is available on the relation of MDSC accumulation with clinical settings in breast cancer patients. The aim of this study was to investigate levels and phenotypes of myeloid cells in peripheral blood (n = 23) and tumor microenvironment of primary breast cancer patients (n = 7), compared with blood from healthy donors (n = 21) and paired non-tumor normal breast tissues from the same patients (n = 7). Using multicolor flow cytometric assays, we found that breast cancer patients had significantly higher levels of tumor-infiltrating myeloid cells, which comprised of granulocytes (P = 0.022) and immature cells that lack the expression of markers for fully differentiated monocytes or granulocytes (P = 0.016). Importantly, this expansion was not reflected in the peripheral blood. The immunosuppressive potential of these cells was confirmed by expression of Arginase 1 (ARG1), which is pivotal for T-cell suppression. These findings are important for developing therapeutic modalities to target mechanisms employed by immunosuppressive cells that generate an immune-permissive environment for the progression of cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-017-1977-z) contains supplementary material, which is available to authorized users.

Preferential accumulation of regulatory T cells with highly immunosuppressive characteristics in breast tumor microenvironment

“…A significant increase in the levels of CD45 + CD3 − cells within tumor tissue in our study also indicated the presence of cells of myeloid origin including MDSC and neutrophils that play important roles in suppressing host immune responses against cancer, and hence promote cancer progression. We have recently reported an accumulation of myeloid cells in the TME but not in peripheral blood of this PBC patients’ cohort [30]. …”

Therapeutic prospects of targeting myeloid‐derived suppressor cells and immune checkpoints in cancer

“…Numerous studies have reported expansion of MDSC in various human cancers including breast, colon, lung, pancreatic, renal, esophageal and melanomas . We have also previously shown an accumulation of myeloid cells in the TME of breast cancer patients and in the TME and periphery of colorectal cancer patients, which correlated with poorly differentiated tumors . Moreover, elevated levels of MDSC have also been frequently associated with disease progression and reduced survival in several malignancies .…”

“…These pathways are well documented and several therapeutic agents have been developed to target them . Figure shows our previously reported results showing an expansion of myeloid cells and terminally exhaustive T cells, with high expressions of CD25, CD39, PD‐1 and CTLA‐4 in the TME of breast cancer patients …”

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].…”