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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 4  |  Page : 1093-1100

Immunosuppressive effects and mechanisms of three myeloid-derived suppressor cells subsets including monocytic-myeloid-derived suppressor cells, granulocytic-myeloid-derived suppressor cells, and immature-myeloid-derived suppressor cells


1 Department of Medicine, Division of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine, Chuo-ku, Kobe, Japan
2 Department of Medicine, Division of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine; Cancer Center, Kobe University Hospital, Chuo-ku, Kobe, Japan
3 Department of Surgery, Division of Gastrointestinal Surgery, Kobe University Hospital and Graduate School of Medicine, Chuo-ku, Kobe, Japan

Date of Submission22-Aug-2020
Date of Acceptance21-Jan-2021
Date of Web Publication14-Sep-2021

Correspondence Address:
Yohei Funakoshi
Department of Medicine, Division of Medical Oncology/Hematology, Kobe University Hospital and Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1222_20

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 > Abstract 


Context: Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immune cells of myeloid lineage. Recent reports have suggested that human MDSC are divided into three subsets: monocytic MDSC (M-MDSC), granulocytic MDSC (G-MDSC), and immature MDSC (I-MDSC). However, the characteristics of each human MDSC subset still remain unclear.
Materials and Methods: To evaluate the immunosuppressive effects and mechanisms, we first performed a T-cell suppression assay using cells obtained from healthy donor peripheral blood samples. The levels of immune inhibitory molecules in the culture supernatant of each MDSC subset were measured to reveal the T-cell suppressive mechanisms. Then, we compared these results with the results from cells obtained from cancer patient blood samples. Finally, we investigated the difference in the frequency of each MDSC subset between the healthy donors and the cancer patients.
Results: Although M-MDSC and G-MDSC suppressed T-cell activation, I-MDSC had no T-cell suppressive effect. We found that the culture supernatant of M-MDSC and G-MDSC contained high levels of interleukin-1 receptor antagonist (IL-1RA) and arginase, respectively, in both healthy donors and cancer patients. No inhibitory molecules were detected in the culture supernatant of I-MDSC. The population of functional MDSC (M-MDSC and G-MDSC) in the total MDSC was significantly increased in cancer patients compared with that in healthy donors.
Conclusions: Although M-MDSC and G-MDSC, which released IL-1RA and arginase, respectively, suppressed T-cell activation, I-MDSC did not have an immunosuppressive effect. The population of functional MDSC was increased in cancer patients compared with that in healthy donors.

Keywords: Cancer patients, interleukin-1 receptor antagonist, myeloid-derived suppressor cells, three myeloid-derived suppressor cells subsets


How to cite this article:
Nagatani Y, Funakoshi Y, Suto H, Imamura Y, Toyoda M, Kiyota N, Yamashita K, Minami H. Immunosuppressive effects and mechanisms of three myeloid-derived suppressor cells subsets including monocytic-myeloid-derived suppressor cells, granulocytic-myeloid-derived suppressor cells, and immature-myeloid-derived suppressor cells. J Can Res Ther 2021;17:1093-100

How to cite this URL:
Nagatani Y, Funakoshi Y, Suto H, Imamura Y, Toyoda M, Kiyota N, Yamashita K, Minami H. Immunosuppressive effects and mechanisms of three myeloid-derived suppressor cells subsets including monocytic-myeloid-derived suppressor cells, granulocytic-myeloid-derived suppressor cells, and immature-myeloid-derived suppressor cells. J Can Res Ther [serial online] 2021 [cited 2021 Dec 7];17:1093-100. Available from: https://www.cancerjournal.net/text.asp?2021/17/4/1093/325932




 > Introduction Top


Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that are potent suppressors of immune cell function.[1],[2] An inflammatory response in cancer tissue triggers the expansion of MDSC in the bone marrow and the spleen. Subsequently, these MDSC accumulate in the peripheral blood, lymphoid organs, parenchymal organs, and tumors.[3] MDSC are known to suppress the antitumor immune response and promote tumor growth and metastasis.[4] In cancer patients, an increased number of MDSC in the peripheral blood has been reported to be associated with poor prognosis, and it has become clear that MDSC are clinically relevant to cancer patient survival.[5]

MDSC represent a heterogeneous population.[4],[6] In general, MDSC can be divided into two major subsets, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC), based on morphological and phenotypic differences. M-MDSC and G-MDSC are morphologically similar to monocytes and neutrophils, respectively.[6] Originally, MDSC were found in the peripheral blood, lymphoid organs, and tumor tissue of tumor-bearing mice. In mice, total MDSC are defined as cells expressing both the Gr-1 and CD11b markers. M-MDSC are defined as CD11b+ Ly6G Ly6Chigh and G-MDSC as CD11b+ Ly6G+ Ly6Clow cells.[7],[8],[9] To mirror these findings in mice, human total MDSC are broadly characterized by surface protein expression of CD11b+ CD33+ Lin HLA-DR−/low and are divided into two subsets, CD14+ CD15 MDSC (M-MDSC) and CD14 CD15+ MDSC (G-MDSC); these cells are found among the peripheral blood mononuclear cells (PBMC) isolated by Ficoll density gradient centrifugation.[10] Recently, a third population of human MDSC was identified as a group of more immature progenitor CD14 CD15 MDSC, and it has been proposed that these cells be called immature or early-stage MDSC (I-MDSC or e-MDSC).[2],[11]

Although MDSC is implicated in the suppression of many different immune system cells, the main target of MDSC is T-cells.[12] Decades of MDSC discovery has indicated that MDSC can suppress T-cell activation by multiple mechanisms, mostly through the production of immunosuppressive metabolic enzymes (e.g., arginase, indoleamine 2,3-dioxygenase [IDO], and inducible nitric oxide synthase [iNOS]), cytokines (e.g., transforming growth factor β and interleukin-10 [IL-10]), and many others.[2],[13],[14],[15] These findings have improved our understanding of MDSC; however, these results were mainly obtained in mice experiments. As research results regarding MDSC in mice are not always applicable to humans, further research using human samples is necessary. In particular, details of the immunosuppressive effects and the mechanisms of action of each human MDSC subset (M-MDSC, G-MDSC, and I-MDSC) require further elucidation.

In the current research, we evaluated the immunosuppressive effects of M-MDSC, G-MDSC, and I-MDSC using human healthy donor blood samples. In terms of the immunosuppressive mechanisms, we measured several immune inhibitory molecules (cytokines and metabolic enzymes) in the culture supernatant of each MDSC subset. We then examined whether the same immunosuppressive effects and mechanisms could be observed in culture supernatants of cells from cancer patient blood samples. Finally, we investigated the relative frequencies of total MDSC and each MDSC subset in cancer patient samples and compared them with those in healthy donor samples.


 > Materials and Methods Top


Flow cytometric analysis and cell sorting

Heparin-containing tubes were used to collect peripheral blood samples from healthy donors and cancer patients. Then, PBMC were separated from the peripheral blood by density gradient centrifugation method using Ficoll-Paque Plus medium and SepMate-50 tubes (STEMCELL Technologies).

The PBMC were stained for 20 min at 4°C with the following anti-human antibodies: lineage marker (Lin) (CD3, CD19, CD20, CD56 PE [BD Biosciences]), HLA-DR PerCP (BD Biosciences), CD11b BV710 (BD Biosciences), CD33 BB515 (BD Biosciences), CD14 BV421 (BD Biosciences), and CD15 BV510 (BD Biosciences). Isotype-matched antibodies were used as controls. Flow cytometric analysis was performed using a BD LSRFortessa X-20 device, and cell sorting was performed using a FACSAria III instrument (BD Biosciences). The data were analyzed with FlowJo software (BD Biosciences).

We used the established phenotypes for the MDSC analysis.[11],[16],[17],[18],[19],[20],[21],[22],[23] CD11b + CD33 + Lin HLA-DR−/low cells were defined as total MDSC. Then, the total MDSC were divided into three subsets including M-MDSC (CD11b+ CD33+ Lin HLA-DR−/lowCD14+ CD15), G-MDSC (CD11b+ CD33+ Lin HLA-DR−/lowCD14 CD15+), and I-MDSC (CD11b+ CD33+ Lin HLA-DR−/lowCD14 CD15).

T-cell suppression assay

Healthy donor CD3+ T cells were isolated using the Human T-Cell Isolation Kit (STEMCELL Technologies) and stained with CellTrace Violet (Thermo Fisher Scientific). The total MDSC and each MDSC subset that had been obtained by sorting healthy donor sample with a FACSAria III were cocultured with the stained CD3+ T cells (1 × 105 cells) at 1:1, 0.5:1, 0.33:1, 0.2:1, and 0.1:1 ratios in a 96-well flat-bottom plate (Corning). Dynabeads Human T-Activator CD3/CD28 (Invitrogen) were then immediately added to the CD3+ T cells at a 1:1 ratio to induce T cell activation. After 3 days of coculture at 37°C and 5% CO2, the CD3+ T cells were harvested and analyzed by flow cytometry using a FACSVerse device (BD Biosciences). CD3+ T cell division was measured by Violet dilution. In addition, CD3+ T cell cluster formations under the previously stated experimental conditions were evaluated using a BZ-X700 All-in-one Fluorescence Microscope (KEYENCE).

The interferon-gamma (IFN-γ concentrations in the supernatants of the 3-day cocultures were determined with a Human ELISA Kit according to the manufacturer's protocol (RandD SYSTEMS).

Cytokine and enzyme analysis in the culture supernatant

Each sorted MDSC subset was cultured in T-Cell Expansion SFM medium (Thermo Fisher Scientific) for 3 days. The concentrations of cytokines and enzymes in the culture supernatant were measured by the following methods.

The immune inhibitory molecule IDO concentration in the culture supernatant was determined with the Human ELISA Kit (R and D SYSTEMS) mentioned previously. LEGENDplex (BioLegend), a bead-based immunoassay that uses the same basic principles as a sandwich immunoassay, was used to measure IL-1 receptor antagonist (IL-1RA), arginase, IL-4, IL-5, IL-10, IL-11, IL-13, and C-C motif chemokine ligand 17 (CCL17; also known as TARC) in the culture supernatant. The capture bead with the antibody for the particular molecule conjugated on its surface was mixed with the culture supernatant and the mixture was incubated for 2 h. After washing, biotinylated detection antibodies were added and the sample was incubated for 1 h so that capture bead–molecule–detection antibody sandwiches were formed. Streptavidin-phycoerythrin (SA-PE) was subsequently added and the samples were incubated for 30 min. For each bead population, the PE signal fluorescence intensity was then quantified using a BD LSRFortessa X-20 cell analyzer. The concentration of a particular molecule was determined based on a known standard curve using the LEGENDplex data analysis software.

Evaluation of CD3+ T cell suppression by interleukin-1 receptor antagonist

The CD3+ T cells (1 × 105 cells) in a 96-well flat-bottom plate were stimulated with Dynabeads at a 1:1 ratio and recombinant human IL-1-receptor antagonist (rhIL-1RA) (FUJIFILM Wako Pure Chemical Corporation) was added in each well at three concentrations of 0, 100, and 1000 ng/mL. After 2 days of culture at 37°C and 5% CO2, the IFN-γ concentration in the culture supernatant was determined with the Human ELISA Kit mentioned previously. In addition, CD3+ T cell cluster formations under the previously described experimental conditions were evaluated by the fluorescence microscope mentioned previously.

Ethics approval and consent to participate

Cancer patient blood samples were obtained with the patient's consent from cancer patients who visited Kobe University Hospital. All patients provided written informed consent for this investigation. The investigation was approved by the Kobe University Hospital Ethics Committee (No. 180152) and conducted in accordance with the Declaration of Helsinki.

Statistical analysis

Error bars indicated standard deviation (SD) and results were presented as mean values ± SD Statistical analysis was performed using two-tailed Student's t-tests and values of P < 0.05 were statistically significant. P values are indicated in the figure legends.


 > Results Top


Phenotypic characterization of each myeloid-derived suppressor cells subset (monocytic-myeloid-derived suppressor cells, granulocytic-myeloid-derived suppressor cells, and immature-myeloid-derived suppressor cells) in the peripheral blood of healthy donors

Total MDSC (CD11b+ CD33+ Lin HLA-DR−/low) were identified according to the gating strategy in [Figure 1]a. In addition, each previously reported MDSC subset was characterized by the monocytic marker CD14 and the myeloid marker CD15.
Figure 1: Gating strategy and May-Giemsa staining for human total myeloid-derived suppressor cells and each myeloid-derived suppressor cells subset in peripheral blood mononuclear cells. (a) Gating strategy by flow cytometric analysis. (b) May-Giemsa stain, and the cytological characteristics by microscopic analysis

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Each MDSC subset was stained by May-Giemsa staining. The M-MDSC had large, horseshoe-shaped nuclei similar to those of monocytes, and the G-MDSC were polymorphonuclear similar to neutrophils. The I-MDSC had an immature form with a high nucleus/cytoplasm ratio and small size [Figure 1]b.

Monocytic-myeloid-derived suppressor cells and granulocytic-myeloid-derived suppressor cells suppressed T-cell activation, whereas immature-myeloid-derived suppressor cells had no suppressive effect on T cell activation

As we expected, the total MDSC and M-MDSC caused cell concentration-dependent suppression of CD3+ T cell proliferation [Figure 2]a. In contrast, the I-MDSC did not suppress CD3+ T cell proliferation at any ratio of I-MDSC to CD3+ T cells [Figure 2]a. Because the population of G-MDSC was smaller than those of M-MDSC and I-MDSC in healthy donor samples, the G-MDSC were cocultured with CD3+ T cells at 0.5:1, 0.2:1, and 0.1:1 ratios [Figure 2]b. The G-MDSC also suppressed the CD3+ T cell proliferation [Figure 2]b. In addition, the total MDSC, M-MDSC, and G-MDSC clearly inhibited the CD3+ T cell cluster formations indicating T-cell proliferation under fluorescence microscope examination [Figure 2]c and [Figure 2]d, while the I-MDSC did not inhibit cluster formations [Figure 2]c.
Figure 2: Suppression of T cell activation by total MDSC and each myeloid-derived suppressor cells subset. (a and b) After 3 days of culture, the percentage of T cell proliferation was determined by flow cytometric analysis of Violet dilution. (c and d) The CD3 + T cell cluster formations were observed by fluorescence microscope. These samples were analyzed after 3 days of coculture

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IFN-γ is released in large amounts by activated T-cells. The total MDSC, M-MDSC, and G-MDSC suppressed IFN-γ release from T-cells that were stimulated with Dynabeads [Figure 3]. In contrast, the I-MDSC did not suppress IFN-γ production [Figure 3].
Figure 3: Protein assay for IFN-γ by ELISA

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These results demonstrated that the total MDSC, M-MDSC, and G-MDSC strongly suppress T-cell activation, whereas the I-MDSC do not suppress T cell activation.

The monocytic-myeloid-derived suppressor cells released interleukin-1 receptor antagonist whereas the granulocytic-myeloid-derived suppressor cells released arginase

To reveal the mechanism of the T cell suppression by MDSC, several cytokines (IL-1RA, IL-4, IL-5, IL-10, IL-11, IL-13, and CCL17) and metabolic enzymes (arginase and IDO) that have been reported as immune inhibitory molecules were measured in the culture supernatant of each MDSC subset. IL-1RA was notably increased in the culture supernatant of the M-MDSC, and arginase was notably increased in the culture supernatant of the G-MDSC [Figure 4]. In terms of the I-MDSC, no or little production of any immune inhibitory molecules was detected. Although arginase is well known as a molecule responsible for the T cell suppression by MDSC, little is known about the relationship between IL-1RA and the T cell suppression by MDSC. To confirm the suppressive ability of IL-1RA, we evaluated whether rhIL-1RA suppressed the IFN-γ release from T-cells that were stimulated with Dynabeads [Figure 5]a. The rhIL-1RA suppressed IFN-γ production in a concentration-dependent manner. In the same way, rhIL-1RA clearly inhibited cluster formations of stimulated CD3+ T cells [Figure 5]b.
Figure 4: Protein assay for immune inhibitory molecules by ELISA. Cultured for 3 days. Data from three independent samples from healthy donors are shown. ND: not detected

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Figure 5: CD3+ T cell suppression by rh interleukin-1 receptor antagonist. (a) After 2 days of culture, the IFN-g released from the CD3+ T cells was measured by ELISA. Data are shown from three experiments. *P < 0.05, **P < 0.01. (b) CD3+ T cell cluster formations were observed by the fluorescence microscope. These samples were analyzed after 2 days of coculture

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No significant release of IL-4, IL-5, IL-10, IL-11, IL-13, or CCL17 was found in any of the subsets, and the IDO concentration increased slightly in the M-MDSC and G-MDSC as previously reported [Figure 4].[24],[25],[26]

The myeloid-derived suppressor cells from cancer patients had the same characteristics as the myeloid-derived suppressor cells from healthy donors

We evaluated whether the MDSC from advanced cancer patients had the same characteristics as those from healthy donors by performing the same analyses. The same subsets (M-MDSC, G-MDSC, and I-MDSC) were confirmed in cancer patient samples by flow cytometric analysis. In terms of T cell suppression, the same tendency was observed. Although the total MDSC, M-MDSC, and G-MDSC from cancer patients suppressed IFN-γ release from stimulated T-cells, the I-MDSC did not suppress IFN-γ production [Figure 6]a. Furthermore, as with healthy donor cells, the M-MDSC from cancer patients released IL-1RA, and the G-MDSC from cancer patients released arginase [Figure 6]b. These results indicated that the MDSC from cancer patients had the same characteristics as those from healthy donors.
Figure 6: Verification of T cell suppressive effects and mechanisms by cancer patient myeloid-derived suppressor cells. The following analyses were performed by using cancer patient blood samples: (a) After 3 days of culture, the IFN-g concentrations were measured with the Human ELISA Kit. (b) Protein assay for immune inhibitory molecules by ELISA after 3 days of culture. Data from three independent samples are shown. ND: not detected

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The population of functional myeloid-derived suppressor cells (monocytic-myeloid-derived suppressor cells and granulocytic-myeloid-derived suppressor cells) was increased in cancer patients compared with that in healthy donors

Analyses of the MDSC from healthy donors (n = 8) and patients with advanced cancers (n = 8) [Table S1] were performed. The proportion of total MDSC in the PBMC was significantly increased in cancer patients compared to that in healthy donors [Figure 7]a. In a subset analysis, the proportion of functional MDSC (M-MDSC and G-MDSC) in the total MDSC was significantly increased in the cancer patients compared with that in healthy donors [Figure 7]b. These results suggested that the MDSC population in cancer patients was more immunosuppressive than that in healthy donors.
Figure 7: Comparison of total myeloid-derived suppressor cells and each myeloid-derived suppressor cells subset between healthy donors and cancer patients. (a) The percentages of total myeloid-derived suppressor cells in peripheral blood mononuclear cells are shown. Those of cancer patients (n = 8) were significantly higher than those of healthy donors (n = 8). ***P < 0.001. (b) The percentages of I-MDSC and combined monocytic-myeloid-derived suppressor cells and granulocytic-myeloid-derived suppressor cells in total myeloid-derived suppressor cells are shown. The percentage of combined monocytic-myeloid-derived suppressor cells and granulocytic-myeloid-derived suppressor cells in samples from cancer patients (n = 8) was significantly greater than that in samples from healthy donors (n = 8). ***P < 0.001

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 > Discussion Top


Recommendations have recently been proposed for the characterization of three human MDSC subsets. Based on these previous reports,[2],[11] we characterized three subsets of MDSC: M-MDSC (CD11b + CD33 + Lin HLA-DR−/lowCD14 + CD15), G-MDSC (CD11b + CD33 + Lin HLA-DR−/lowCD14 CD15+), and I-MDSC (CD11b + CD33 + Lin HLA-DR−/lowCD14 CD15) and performed experiments to reveal the immunosuppressive effects and mechanisms of each human MDSC subset.

The suppression assay of T cell proliferation was performed with the total MDSC and each MDSC subset, and it was confirmed that the total MDSC, M-MDSC, and G-MDSC had an immunosuppressive effect. However, the I-MDSC were found to have no immunosuppressive effect. As the mechanisms of the immunosuppression, we found that the M-MDSC and G-MDSC excrete IL-1RA and arginase, respectively. In contrast, we did not detect immune inhibitory molecules in the culture supernatant of the I-MDSC. The same results were observed for cells from healthy donors and cancer patients.

IL-1 is a highly pro-inflammatory cytokine that is widely produced by various cells including monocytes, dendritic cells, neutrophils, T-cells, macrophages, and endothelial cells. Stimulating the IL-1 receptor on T-cells has been shown to enhance T cell proliferation. IL-1RA is a member of the IL-1 family that binds to the IL-1 receptor but does not induce any discernible intracellular response.[27] Because IL-1 receptor signaling strongly activates the inflammatory pathways of T cells, IL-1RA can suppress T cell activity as a competitive inhibitor of the IL-1 receptor.[27] In fact, CD3 + T cell proliferation stimulated by Dynabeads was suppressed in a concentration-dependent manner by adding rhIL-1RA [Figure 5]a and [Figure 5]b. Very few studies have reported a relationship between IL-1RA and MDSC. Although a study group reported that total MDSC released IL-1RA in mice,[28] the relationship between IL-1RA and human MDSC is not known. To our knowledge, this is the first report confirming that IL-1RA was produced by human MDSC, and importantly, only M-MDSC were identified as an IL-1RA-producing subset.

Arginase depletes L-arginine, restricting T cell proliferation. Arginase has already been well identified as one of the key factors for T cell suppression by both mice and human MDSC. Recent studies using clinical samples have demonstrated that the G-MDSC are the main MDSC subset producing arginase.[29],[30] Consistent with these previous reports, we detected high levels of arginase only in the culture supernatant of the G-MDSC.

I-MDSC are the most recent concept in the three subsets.[11],[19] In contrast to the other two conventional subsets, the functions of I-MDSC are poorly understood. Even the immunosuppressive ability of I-MDSC is still controversial. One study group suggested that I-MDSC could moderately suppress immunity.[2] On the other hand, another group showed that I-MDSC only had a much smaller immunosuppressive ability compared with those of M-MDSC and G-MDSC.[30] In this study, the I-MDSC did not suppress T cell proliferation. Furthermore, the I-MDSC also did not suppress INF-γ release from activated T-cells. These results indicated that the I-MDSC did not have an immunosuppressive effect. Notably, although we detected IL-1RA and arginase as immune inhibitory molecules in the culture supernatants of the M-MDSC and G-MDSC, respectively, no immunosuppressive molecules including IL-1RA and arginase were detected in the culture supernatant of the I-MDSC in our study.

Even in healthy people, a small population of cells with immunosuppressive function exists to maintain homeostasis and balanced immunity. However, some effects of tumor cells disrupt this homeostasis, leading to an increase in the cell populations with immunosuppressive function.[31],[32] In recent years, the clinical role of MDSC in cancer patients has been a focus of study. Many studies monitored the total MDSC in various types of cancer, and revealed a significant increase in the total MDSC in the peripheral blood in the breast, bladder, thyroid, head and neck, and non-small cell lung cancer patients compared with levels in healthy donors.[5],[19],[18],[30],[33],[34],[35],[36],[37] In a meta-analysis, the total MDSC counts in the peripheral blood were found to be an independent indicator of poor outcomes in subjects with solid tumors.[38] Consistent with previous reports,[5],[19],[30],[33],[34],[35],[36],[37] the total MDSC level was significantly higher in cancer patients than in healthy donors in our study. In particular, the percentages of functional MDSC (M-MDSC and G-MDSC) in the total MDSC were significantly increased in cancer patients compared with the percentages in healthy donors. Because the immune system can be suppressed in cancer patients, these results are reasonable. Based on these findings, we suggest that functional MDSC are an important population for suppressing immunity in cancer patients and a potential therapeutic target in cancer.


 > Conclusions Top


We found that the M-MDSC and G-MDSC suppressed T cell activation, but that the I-MDSC did not. We also showed for the first time that the M-MDSC released IL-1RA, which is an immune inhibitory molecule. In addition, we confirmed that percentages of functional MDSC (M-MDSC and G-MDSC) are increased in cancer patients compared with percentages in healthy donors.

Financial support and sponsorship

This research was supported by the Kinki Promotion Network for Clinical Oncology under Grant Number 201704. The funder of this study had no role in the study design, data collection, analysis, interpretation of data, and writing of the manuscript.

Conflicts of interest

There are no conflicts of interest.



 
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]



 

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