CD66b+ monocytes represent a proinflammatory myeloid subpopulation in cancer

Horzum, Utku; Yöyen-Ermiş, Diğdem; Taşkıran, Ekim Z.; Yılmaz, Kerim Bora; Hamaloğlu, Erhan; Karakoç, Derya; Esendağlı, Güneş

doi:10.1007/s00262-020-02656-y

Cited by 18 publications

(6 citation statements)

References 60 publications

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“… 54 55 CyTOF analysis revealed increased iMo infiltration ( figure 5E ) and CD66b expression of iMos ( figure 5B ) in tumor tissues compared with normal tissues. Previous studies have suggested that CD66b + monocytes are a proinflammatory myeloid cell subset in cancer, 56 and the enrichment of this subset in ESCA is consistent with the reports that ESCA is an inflammatory tumor. 5 6 Through CyTOF analysis, we found that iMos in tumors simultaneously expressed higher levels of the cDC2 markers CD11c and CD1c ( figures 5C and 6H ).…”

Section: Resultssupporting

confidence: 89%

Hypoxia inhibits the iMo/cDC2/CD8+ TRMs immune axis in the tumor microenvironment of human esophageal cancer

Wu,

Yu,

Liang

et al. 2024

J Immunother Cancer

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BackgroundEsophageal cancer (ESCA) is a form of malignant tumor associated with chronic inflammation and immune dysregulation. However, the specific immune status and key mechanisms of immune regulation in this disease require further exploration.MethodsTo investigate the features of the human ESCA tumor immune microenvironment and its possible regulation, we performed mass cytometry by time of flight, single-cell RNA sequencing, multicolor fluorescence staining of tissue, and flow cytometry analyses on tumor and paracancerous tissue from treatment-naïve patients.ResultsWe depicted the immune landscape of the ESCA and revealed that CD8+(tissue-resident memory CD8+T cells (CD8+TRMs) were closely related to disease progression. We also revealed the heterogeneity of CD8+TRMs in the ESCA tumor microenvironment (TME), which was associated with their differentiation and function. Moreover, the subset of CD8+TRMs in tumor (called tTRMs) that expressed high levels of granzyme B and immune checkpoints was markedly decreased in the TME of advanced ESCA. We showed that tTRMs are tumor effector cells preactivated in the TME. We then demonstrated that conventional dendritic cells (cDC2s) derived from intermediate monocytes (iMos) are essential for maintaining the proliferation of CD8+TRMs in the TME. Our preliminary study showed that hypoxia can promote the apoptosis of iMos and impede the maturation of cDC2s, which in turn reduces the proliferative capacity of CD8+TRMs, thereby contributing to the progression of cancer.ConclusionsOur study revealed the essential antitumor roles of CD8+TRMs and preliminarily explored the regulation of the iMo/cDC2/CD8+TRM immune axis in the human ESCA TME.

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Section: Resultssupporting

confidence: 89%

Hypoxia inhibits the iMo/cDC2/CD8+ TRMs immune axis in the tumor microenvironment of human esophageal cancer

Wu,

Yu,

Liang

et al. 2024

J Immunother Cancer

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“…The results showed that ALA significantly increased the production of CD71 + GPA + erythrocytes (28.5 ± 2.0% vs. 11.9 ± 0.5%) gated from CD11b – cells. At the same time, ALA increased the production of CD66b – CD14 + monocytes, while decreased the production of CD66b + CD14 – neutrophils [ 20 ] and CD66b + CD14 + proinflammatory monocytes [ 33 ] or antigen-presenting cells (APCs)-like tumor associate neutrophil like cells [ 34 ] derived from CD34 + HSPCs (Fig. 1 B, C).…”

Section: Resultsmentioning

confidence: 99%

Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation

Zhang,

Zhou,

et al. 2024

Stem Cell Res Ther

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Background Erythroid and myeloid differentiation disorders are commonly occurred in leukemia. Given that the relationship between erythroid and myeloid lineages is still unclear. To find the co-regulators in erythroid and myeloid differentiation might help to find new target for therapy of myeloid leukemia. In hematopoiesis, ALA (alpha lipoic acid) is reported to inhibit neutrophil lineage determination by targeting transcription factor ELK1 in granulocyte-monocyte progenitors via splicing factor SF3B1. However, further exploration is needed to determine whether ELK1 is a common regulatory factor for erythroid and myeloid differentiation. Methods In vitro culture of isolated CD34+, CMPs (common myeloid progenitors) and CD34+ CD371– HSPCs (hematopoietic stem progenitor cells) were performed to assay the differentiation potential of monocytes, neutrophils, and erythrocytes. Overexpression lentivirus of long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 transduced CD34+ HSPCs were transplanted into NSG mice to assay the human lymphocyte and myeloid differentiation differences 3 months after transplantation. Knocking down of SRSF11, which was high expressed in CD371+GMPs (granulocyte-monocyte progenitors), upregulated by ALA and binding to ELK1-RNA splicing site, was performed to analyze the function in erythroid differentiation derived from CD34+ CD123mid CD38+ CD371– HPCs (hematopoietic progenitor cells). RNA sequencing of L-ELK1 and S-ELK1 overexpressed CD34+ CD123mid CD38+ CD371– HPCs were performed to assay the signals changed by ELK1. Results Here, we presented new evidence that ALA promoted erythroid differentiation by targeting the transcription factor ELK1 in CD34+ CD371– hematopoietic stem progenitor cells (HSPCs). Overexpression of either the long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 inhibited erythroid-cell differentiation, but knockdown of ELK1 did not affect erythroid-cell differentiation. RNAseq analysis of CD34+ CD123mid CD38+ CD371– HPCs showed that L-ELK1 upregulated the expression of genes related to neutrophil activity, phosphorylation, and hypoxia signals, while S-ELK1 mainly regulated hypoxia-related signals. However, most of the genes that were upregulated by L-ELK1 were only moderately upregulated by S-ELK1, which might be due to a lack of serum response factor interaction and regulation domains in S-ELK1 compared to L-ELK1. In summary, the differentiation of neutrophils and erythrocytes might need to rely on the dose of L-ELK1 and S-ELK1 to achieve precise regulation via RNA splicing signals at early lineage commitment. Conclusions ALA and ELK1 are found to regulate both human granulopoiesis and erythropoiesis via RNA spliceosome, and ALA-ELK1 signal might be the target of human leukemia therapy.

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“…Neutrophil infiltrates and fibroblast activation: CD66b is an antigenic marker of tumor-infiltrating neutrophils, representing proinflammatory myeloid infiltrates 66,67 . Infiltrating neutrophils seem to increase cancer invasion, lymph node metastasis, and tumor stage 68,69 .…”

Section: Paradoxical Role Of Immune Suppression In Crcmentioning

confidence: 99%

Identification of Spatial Proteomic Signatures of Colon Tumor Metastasis: A Digital Spatial Profiling Approach

Levy

Zavras

Veziroglu

et al. 2022

Preprint

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Over 150,000 Americans are diagnosed with colorectal cancer (CRC) every year, and annually over 50,000 individuals will die from CRC, necessitating improvements in screening, prognostication, disease management, and therapeutic options. CRC tumors are removed en bloc with surrounding vasculature and lymphatics. Examination of regional lymph nodes at the time of surgical resection is essential for prognostication. Developing alternative approaches to indirectly assess recurrence risk would have utility in cases where lymph node yield is incomplete or inadequate. Spatially dependent, immune cell-specific (e.g., Tumor Infiltrating Lymphocytes- TILs), proteomic, and transcriptomic expression patterns inside and around the tumor - the tumor immune microenvironment (TIME) - can predict nodal/distant metastasis and probe the coordinated immune response from the primary tumor site. The comprehensive characterization of TILs and other immune infiltrates is possible using highly multiplexed spatial omics technologies, such as the GeoMX Digital Spatial Profiler (DSP). In this study, machine learning and differential co-expression analyses helped identify biomarkers from DSP-assayed protein expression patterns inside, at the invasive margin, and away from the tumor, associated with extracellular matrix remodeling (e.g., GZMB, fibronectin), immune suppression (e.g., FOXP3), exhaustion and cytotoxicity (e.g., CD8), PD-L1 expressing dendritic cells, neutrophil proliferation, amongst other concomitant alterations. Further investigation of these biomarkers may reveal independent risk factors of CRC metastasis that can be formulated into low-cost, widely available assays.

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CD66b+ monocytes represent a proinflammatory myeloid subpopulation in cancer

Cited by 18 publications

References 60 publications

Hypoxia inhibits the iMo/cDC2/CD8+ TRMs immune axis in the tumor microenvironment of human esophageal cancer

Hypoxia inhibits the iMo/cDC2/CD8+ TRMs immune axis in the tumor microenvironment of human esophageal cancer

Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation

Identification of Spatial Proteomic Signatures of Colon Tumor Metastasis: A Digital Spatial Profiling Approach

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