Myeloid-derived cells (MDCs) are crucial in immune response and tissue homeostasis. They have high functional plasticity and can be polarized according to microenvironment signals. These cells, including macrophages, neutrophils, and dendritic cells (DCs), exhibit different functional polarization states in different pathological environments and are involved in the occurrence and development of diseases such as inflammation and tumors. Studies have shown that metabolic reprogramming plays a key role in the functional polarization of MDCs, affecting the cellular energy supply and regulating immune function. This paper reviews classification, function and polarization mechanism of MDCs and discusses metabolic reprogramming. In addition, the therapeutic strategies targeting MDC are summarized, which is expected to provide new targets for tumor immunotherapy.
Humans ; Tumor Microenvironment/immunology* ; Myeloid Cells/metabolism* ; Neoplasms/pathology* ; Animals ; Immunotherapy/methods* ; Dendritic Cells/immunology* ; Macrophages/immunology*

OBJECTIVE: To explore the effects of hydroxychloroquine (HCQ) on immune mediators dysregulation in severe infection after chemotherapy in acute myeloid leukemia (AML) and its molecular mechanism. METHODS: Bone marrow or peripheral blood samples of 36 AML patients with severe infection (AML-SI) and 29 AML patients without infection (AML-NI) after chemotherapy were collected from the First Affiliated Hospital of Gannan Medical University from August 2022 to June 2023. In addition, the peripheral blood of 21 healthy subjects from the same period in our hospital was selected as the control group. The mRNA expressions of CXCL12, CXCR4 and CXCR7 were detected by RT-qPCR technology, and the levels of IL-6, IL-8 and TNF-α were detected by ELISA. Leukemia-derived THP-1 cells were selected and constructed as AML disease model. At the same time, bone marrow mesenchymal stem cells (BM-MSCs) from AML-SI patients were co-cultured with THP-1 cells and divided into Mono group and Co-culture group. THP-1 cells were treated with different concentration gradients of HCQ. The cell proliferation activity was subsequently detected by CCK-8 method and apoptosis was detected by Annexin V/PI double staining flow cytometry. ELISA was used to detect the changes of IL-6, IL-8 and TNF-α levels in the supernatant of the cell co-culture system, RT-qPCR was used to detect the mRNA expression changes of the core members of the CXCL12-CXCR4/7 regulatory axis, and Western blot was used to detect the expressions of apoptosis regulatory molecules and related signaling pathway proteins. RESULTS: CXCL12, CXCR4, CXCR7, as well as IL-6, IL-8, and TNF-α were all abnormally increased in AML patients, and the increases were more significant in AML-SI patients (P <0.01). Furthermore, there were statistically significant differences between AML-NI patients and AML-SI patients (all P <0.05). HCQ could inhibit the proliferation and induce the apoptosis of THP-1 cells, but the low concentration of HCQ had no significant effect on the killing of THP-1 cells. When THP-1 cells were co-cultured with BM-MSCs of AML patients, the levels of IL-6, IL-8 and TNF-α in the supernatance of Co-culture group were significantly higher than those of Mono group (all P <0.01). After HCQ intervention, the levels of IL-6, IL-8 and TNF-α in cell culture supernatant of Mono group were significantly decreased compared with those before intervention (all P <0.01). Similarly, those of Co-culture group were also significantly decreased (all P <0.001). However, the expression of the core members of the CXCL12-CXCR4/7 regulatory axis was weakly affected by HCQ. HCQ could up-regulate the expression of pro-apoptotic protein Bax, down-regulate the expression of anti-apoptotic protein Bcl-2, as well as simultaneously promote the hydrolytic activation of Caspase-3 when inhibiting the activation level of TLR4/NF-κB pathway, then induce the programmed death of THP-1 cells after intervention. CONCLUSION The core members of CXCL12-CXCR4/7 axis and related cytokines may be important mediators of severe infectious immune disorders in AML patients. HCQ can inhibit cytokine levels to reverse immune mediators dysregulation and suppress malignant biological characteristics of leukemia cells. The mechanisms may be related to regulating the expression of Bcl-2 family proteins, hydrolytically activating Caspase-3 and inhibiting the activation of TLR4/NF-κB signaling pathway.
Humans ; Leukemia, Myeloid, Acute/immunology* ; Hydroxychloroquine/pharmacology* ; Receptors, CXCR4/metabolism* ; Apoptosis/drug effects* ; Tumor Necrosis Factor-alpha/metabolism* ; Chemokine CXCL12/metabolism* ; Interleukin-8/metabolism* ; Interleukin-6/metabolism* ; Receptors, CXCR/metabolism* ; Mesenchymal Stem Cells ; THP-1 Cells

Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.
Humans ; Tumor Microenvironment/immunology* ; Myeloid Cells/immunology* ; Neoplasms/therapy* ; Animals

Recurrence and metastasis remain the leading cause of death in breast cancer patients due to the lack of effective treatment. A microenvironment suitable for cancer cell growth, referred to as pre-metastatic niche (PMN), is formed in distant organs before metastasis occurs. Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells with immunosuppressive effects. They can expand in large numbers in breast cancer patients and participate in the formation of PMN. MDSCs can remodel the extracellular matrix of pulmonary vascular endothelial cells and recruit cancer stem cells to promote the lung metastasis of breast cancer. Furthermore, MDSCs facilitate immune evasion of breast cancer cells to impact the efficacy of immunotherapy. It is proposed that MDSCs represent a potential therapeutic target for the inhibition of recurrence and metastasis in breast cancer. Therapeutic strategies targeting MDSCs have shown promising efficacy in preclinical studies and clinical trials. This review presents a summary of the principal factors involved in the recruitment and activation of MDSCs during the formation of PMN, and outlines MDSCs functions such as immunosuppression and the current targeted therapies against MDSCs, aiming to provide new ideas for the treatment of distant metastases in breast cancer.
Humans ; Myeloid-Derived Suppressor Cells/immunology* ; Breast Neoplasms/immunology* ; Female ; Tumor Microenvironment ; Disease Progression ; Immunotherapy/methods* ; Neoplasm Metastasis ; Neoplastic Stem Cells

Cisplatin and other platinum-based drugs are used frequently for treatment of lung cancer. However, their clinical performance are usually limited by drug resistance or toxic effects. Carnosic acid, a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), has been reported to have several pharmacological and biological activities. In the present study, the combination effect of cisplatin plus carnosic acid on mouse LLC (Lewis lung cancer) xenografts and possible underlying mechanism of action were examined. LLC-bearing mice were treated with intraperitoneal injection with cisplatin, oral gavage with carnosic acid, or combination with cisplatin and carnosic acid, respectively. Combination of carnosic acid and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than drugs alone. Mechanistic study showed that carnosic acid treatment boosted the function of CD8 T cells as evidenced by higher IFN-γ secretion and higher expression of FasL, perforin as well as granzyme B. In the meantime, the proportion of MDSC (myeloid-derived suppressor cells) in tumor tissues were reduced by carnosic acid treatment and the mRNA levels of iNOS2, Arg-1, and MMP9, which are the functional markers for MDSC, were reduced. In conclusion, our study proved that the functional suppression of MDSC by carnosic acid promoted the lethality of CD8 T cells, which contributed to the enhancement of anti-lung cancer effect of cisplatin.
Abietanes ; administration & dosage ; Animals ; Antineoplastic Agents ; administration & dosage ; CD8-Positive T-Lymphocytes ; drug effects ; immunology ; Carcinoma, Lewis Lung ; drug therapy ; genetics ; immunology ; Cell Line, Tumor ; Cisplatin ; administration & dosage ; Drug Synergism ; Humans ; Interferon-gamma ; genetics ; immunology ; Lung Neoplasms ; drug therapy ; genetics ; immunology ; Matrix Metalloproteinase 9 ; genetics ; Mice ; Mice, Inbred C57BL ; Myeloid-Derived Suppressor Cells ; drug effects ; immunology ; Plant Extracts ; administration & dosage ; Rosmarinus ; chemistry

OBJECTIVETo study the role of triggering receptor expressed on myeloid cells-1(TREM-1) in the pathogenesis of Kawasaki disease (KD).

METHODSBased on color Doppler examination results, 45 children with KD were classified into two groups: coronary artery lesions (CAL group) and no coronary artery lesions (NCAL group). Fifteen children with fever caused by respiratory infection (fever control group) and fifteen healthy children (normal control group) served as controls. Real-time fluorescence quantitative PCR was used to detect the expression of TREM-1 mRNA and DNAX-activating protein 12 (DAP12) mRNA in peripheral blood mononuclear cells (PBMC). ELISA was used to detect the expression of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), DAP12, monocyte chemoattractant protein-1(MCP-1), interleukin-8 (IL-8) proteins levels.

RESULTSThe mean serum protein concentrations of sTREM-1 and DAP12 and the expression levels of TREM-1 mRNA and DAP12 mRNA in PBMC in 45 children with KD (KD group) were significantly higher than in the two control groups (P<0.05). The levels of sTREM-1 protein and TREM-1 mRNA in the CAL subgroup were significantly higher than in the NCAL subgroup (P<0.05). The serum protein concentrations of MCP-1 and IL-8 in the KD group were significantly higher than in the two control groups (P<0.05). The MCP-1 protein level in the CAL subgroup was significantly higher than in the NCAL subgroup (P<0.05). In children with KD, there was a positive correlation between serum sTREM-1 and MCP-1 levels (r=0.523, P<0.05).

CONCLUSIONSTREM-1 activation may be involved in the development of KD.

Chemokine CCL2 ; blood ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Interleukin-8 ; blood ; Male ; Membrane Glycoproteins ; blood ; genetics ; physiology ; Mucocutaneous Lymph Node Syndrome ; etiology ; immunology ; RNA, Messenger ; analysis ; Receptors, Immunologic ; blood ; genetics ; physiology ; Triggering Receptor Expressed on Myeloid Cells-1

OBJECTIVETo investigate the role of miR-21 in airway immunologic dysfunction induced by cold air irritation.

METHODSImmortalized human airway epithelial cell lines BEAS-2B and 16HBE cells were cultured in air-liquid phases. The differential expressions of endogenous miR-21, miR-164, and miR-155 in the cells induced by cold air exposure for different time were detected by real-time PCR. The reporter plasmid containing wild-type or mutated 3'UTR of TLR-4 were constructed and co-transfected into BEAS-2B cells or 16HBE cells together with miR-21 mimic, miR-21 mimic control, miR-21 inhibitor, or miR-21 inhibitor control. Following the transfection, dual luciferase reporter assay was performed to verify the action of miR-21 on TLR-4. miR-21 mimic, miR-21 mimic control, miR-21 inhibitor, and miR-21 inhibitor control were transfected via lipofectamine 2000 in BEAS-2B or 16HBE cells that were subsequently exposed to a temperature at 37 degrees celsius; or cold irritation (30 degrees celsius;), and the protein levels of TLR-4/MyD88 were detected by Western blotting.

RESULTSCold irritation caused a time- dependent up-regulation of miR-21 in both BEAS-2B and 16HBE cells (P<0.05) without obviously affecting the expressions of miR-164 and miR-155. Dual luciferase reporter assay demonstrated a direct combination of miR-21 and its target protein TLR-4. The synthesis levels of TLR-4/MyD88 protein were decreased in miR-21 mimic group even at a routine culture temperature (P<0.05), as also seen in cells with cold irritation (P<0.05). Treatment with the miR-21 inhibitor partially attenuated cold irritation-induced down-regulation of TLR-4/MyD88 protein (P<0.05).

CONCLUSIONCold air irritation-induced airway immunologic dysfunction is probably associated with TLR-4/MyD88 down-regulation by an increased endogenic miR-21.

3' Untranslated Regions ; Blotting, Western ; Cell Line ; Cold Temperature ; Down-Regulation ; Epithelial Cells ; immunology ; metabolism ; Humans ; Luciferases ; MicroRNAs ; metabolism ; Myeloid Differentiation Factor 88 ; metabolism ; Real-Time Polymerase Chain Reaction ; Signal Transduction ; Toll-Like Receptor 4 ; metabolism ; Transfection ; Up-Regulation

Granulocyte colony-stimulating factor (G-CSF) is an essential regulator of neutrophil trafficking and is highly expressed in multiple tumors. Myeloid derived suppressor cells (MDSCs) promote neoplastic progression through multiple mechanisms by immune suppression. Despite the findings of G-CSF function in colon cancer progression, the precise mechanism of G-CSF on MDSCs regulation and its blockade effects on tumor growth remains a worthy area of investigation. In this study we observed an overexpression of G-CSF in a mouse colitis-associated cancer (CAC) model, which was consistent with the accumulation of MDSCs in mouse colon tissues. Further in vitro studies demonstrated that G-CSF could promote MDSCs survival and activation through signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, compared with isotype control, anti-G-CSF mAb treatment demonstrated reduced MDSC accumulation, which led to a marked decrease in neoplasm size and number in mice. Our results indicated that G-CSF is a critical regulating molecule in the migration, proliferation and function maintenance of MDSCs, which could be a potential therapeutic target for colitis-associated cancer.
Animals ; Carcinogenesis ; Colitis ; complications ; Colorectal Neoplasms ; complications ; drug therapy ; immunology ; metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Granulocyte Colony-Stimulating Factor ; genetics ; metabolism ; Immunotherapy ; Mice ; Molecular Targeted Therapy ; Myeloid Cells ; immunology ; metabolism ; pathology

Acute graft-versus-host disease (aGVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the mechanisms of aGVHD are not well understood. We aim to investigate the roles of the three angiogenic factors: angiopoietin-1 (Ang-1), Ang-2 and vascular endothelial growth factor (VEGF) in the development of aGVHD. Twenty-one patients who underwent allo-HSCT were included in our study. The dynamic changes of Ang-1, Ang-2 and VEGF were monitored in patients before and after allo-HSCT. In vitro, endothelial cells (ECs) were treated with TNF-β in the presence or absence of Ang-1, and then the Ang-2 level in the cell culture medium and the tubule formation by ECs were evaluated. After allo-HSCT, Ang-1, Ang-2 and VEGF all exhibited significant variation, suggesting these factors might be involved in the endothelial damage in transplantation. Patients with aGVHD had lower Ang-1 level at day 7 but higher Ang-2 level at day 21 than those without aGVHD, implying that Ang-1 may play a protective role in early phase yet Ang-2 is a promotion factor to aGVHD. In vitro, TNF-β promoted the release of Ang-2 by ECs and impaired tubule formation of ECs, which were both weakened by Ang-1, suggesting that Ang-1 may play a protective role in aGVHD by influencing the secretion of Ang-2, consistent with our in vivo tests. It is concluded that monitoring changes of these factors following allo-HSCT might help to identify patients at a high risk for aGVHD.
Acute Disease ; Adolescent ; Adult ; Angiogenesis Inducing Agents ; immunology ; metabolism ; pharmacology ; Angiopoietin-1 ; genetics ; immunology ; pharmacology ; Angiopoietin-2 ; genetics ; immunology ; pharmacology ; Antineoplastic Agents ; therapeutic use ; Female ; Gene Expression Regulation, Neoplastic ; Graft vs Host Disease ; genetics ; immunology ; pathology ; Hematopoietic Stem Cell Transplantation ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; immunology ; Humans ; Leukemia, Myeloid ; genetics ; immunology ; pathology ; therapy ; Lymphoma, Non-Hodgkin ; genetics ; immunology ; pathology ; therapy ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; immunology ; pathology ; therapy ; Retrospective Studies ; Signal Transduction ; Transplantation, Homologous ; Tumor Necrosis Factor-alpha ; pharmacology ; Vascular Endothelial Growth Factor A ; genetics ; immunology

The efficiency of dendritic cell-activated and cytokine-induced killer cell (DC-CIK) therapy on children with acute myeloid leukemia (AML) after chemotherapy was investigated. Mononuclear cells were collected from children achieving complete remission after chemotherapy, cultured in vitro and transfused back into the same patient. Interleukin-2 (IL-2) was injected subcutaneously every other day 10 times at the dose of 1 × 10(6) units. Peripheral blood lymphocyte subsets and minimal residual disease (MRD) were detected by flow cytometry. Function of bone marrow was monitored by methods of morphology, immunology, cytogenetics and molecular biology. The side effects were also observed during the treatment. The average follow-up period for all the 22 patients was 71 months and relapse occurred in two AML patients (9.1%). The percentage of CD3(+)/CD8(+) cells in peripheral blood of 15 patients at the 3rd month after DC-CIK treatment (36.73% ± 12.51%) was dramatically higher than that before treatment (29.20% ± 8.34%, P < 0.05). The MRD rate was >0.1% in 5 patients before the treatment, and became lower than 0.1% 3 months after the treatment. During the transfusion of DC-CIK, side effects including fever, chills and hives appeared in 7 out of 22 (31.82%) cases but disappeared quickly after symptomatic treatments. There were no changes in electrocardiography and liver-renal functions after the treatment. MRD in children with AML can be eliminated by DC-CIK therapy which is safe and has fewer side effects.
Adolescent ; Antineoplastic Agents ; therapeutic use ; Bone Marrow ; drug effects ; immunology ; pathology ; Child ; Child, Preschool ; Cytokine-Induced Killer Cells ; cytology ; immunology ; transplantation ; Dendritic Cells ; cytology ; immunology ; transplantation ; Female ; Humans ; Immunotherapy, Adoptive ; methods ; Injections, Subcutaneous ; Interleukin-2 ; therapeutic use ; Leukemia, Myeloid, Acute ; immunology ; pathology ; therapy ; Male ; Neoplasm, Residual ; Primary Cell Culture ; Recurrence ; Remission Induction ; Treatment Outcome