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. 2021 Apr 19;10(8):1768.
doi: 10.3390/jcm10081768.

Elevated M-MDSCs in Circulation Are Indicative of Poor Prognosis in Diffuse Large B-Cell Lymphoma Patients

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Elevated M-MDSCs in Circulation Are Indicative of Poor Prognosis in Diffuse Large B-Cell Lymphoma Patients

Zhitao Wang et al. J Clin Med. .

Abstract

Myeloid-derived suppressor cells (MDSCs) are defined as negative regulators that suppress the immune response through a variety of mechanisms, which usually cluster in cancer, inflammation, and autoimmune diseases. This study aims to investigate the correlation between M-MDSCs and the clinical features of diffuse large B-cell lymphoma (DLBCL) patients, as well as the possible accumulation mechanism of M-MDSCs. The level of M-MDSCs is significantly increased in newly diagnosed and relapsed DLBCL patients. Regarding newly diagnosed DLBCL patients, the frequency of M-MDSCs is positively correlated with tumor progression and negatively correlated with overall survival (OS). More importantly, the level of M-MDSCs can be defined as a biomarker for a poor prognosis in DLBCL patients. Additionally, interleukin-35 (IL-35) mediates the accumulation of M-MDSCs in DLBCL patients. Anti-IL-35 treatment significantly reduces levels of M-MDSCs in Ly8 tumor-bearing mice. Thus, M-MDSCs are involved in the pathological process of DLBCL. Targeting M-MDSCs may be a promising therapeutic strategy for the treatment of DLBCL patients.

Keywords: diffuse large B-cell lymphoma; immunosuppression; interleukin-35; myeloid-derived suppressor cells; prognosis; tumor progression.

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Conflict of interest statement

All authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The level of M-MDSCs in DLBCL patients. (A) FCM dot plots demonstrate the frequency of M-MDSCs. (B) M-MDSCs in DLBCL patients compared to healthy controls. (C) M-MDSCs in GCB and no-GCB DLBCL patients. (D) M-MDSCs in A and B symptoms in DLBCL patients. HC, healthy control; ND, newly diagnosed. ** p < 0.01.
Figure 2
Figure 2
M-MDSCs were associated with tumor progression in DLBCL patients. (A) M-MDSCs were associated with DLBCL clinical stages. (B) High LDH level DLBCL patients had an increased frequency of M-MDSCs. (C) Newly diagnosed and relapsed patients had higher levels of M-MDSCs than remission patients. (D) The levels of M-MDSCs significantly decreased after therapy. ND, newly diagnosed; Rel, relapsed; Rem, remission. * p < 0.05; ** p < 0.01.
Figure 3
Figure 3
Circulating M-MDSCs was a prognostic factor in DLBCL patients. (A) High IPI score DLBCL patients had an increased frequency of M-MDSCs. (B) M-MDSCs levels were positively associated with the IPI score. (C) M-MDSC levels were negatively correlated with the OS. (D) Short OS were shown in high M-MDSCs groups. The cut-off value is the median of M-MDSC levels. ** p < 0.01.
Figure 4
Figure 4
The levels of IL-35 in DLBCL patients and their effect on M-MDSCs. (A) p35 and (B) EBI3 mRNA expression in DLBCL patients and healthy controls. (C) The concentration of IL-35 in DLBCL patients and healthy controls. (D) IL-35 induced the expansion of M-MDSCs in vitro. (E) FACS dot plots show the proliferation of M-MDSCs induced with IL-35. Pre-cul, pre-culture; ** p < 0.01.
Figure 5
Figure 5
Functional analysis of M-MDSCs on CD4+T cells. (A) CFSE-labeled CD4+T cells were suppressed by M-MDSCs, (B) associated with a reduction of IFN-γ. (C) A flow cytometry histogram shows the suppressive activity of M-MDSCs. Ctrl, control, ** p < 0.01.
Figure 6
Figure 6
Effect of IL-35 on M-MDSC expansion in vivo. (A) Schematic representation of the experimental design. (B) Anti-IL-35 treatment reduced levels of IL-35. (C) Anti-IL-35 blocked the M-MDSC expansion in vivo. (D) Flow cytometry dot plots show the level of M-MDSCs in the three groups (P4 region). ** p < 0.01.

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