Association of CXCR2+ granulocytic myeloid derived suppressor cells with the development of cholangiocarcinoma: A possible target for intervention.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 565-565
Author(s):  
Nicholas A. Ullman ◽  
Luis I. Ruffolo ◽  
Katherine M. Jackson ◽  
Alexander Chacon ◽  
Rachel Jewell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Disease ◽  
Flow Cytometric Analysis ◽  
Suppressor Cells ◽  
Normal Liver ◽  
Myeloid Derived Suppressor Cells ◽  
Hepatic Tumors ◽  
Liver Malignancy ◽  
Normal Littermate ◽  
Flow Cytometric

565 Background: Cholangiocarcinoma (CCA) is the second most common primary liver malignancy, with increasing incidence. Currently, surgical resection offers the only chance for cure, however the prognosis remains poor in part due to high rates of unresectability, recurrence, and poor response to conventional therapy. Thus, new systemic therapies represent an unmet medical need. Few preclinical models exist for identifying and testing new targeted or immune based therapies. Here we present our findings of the immune infiltrate in human CCA tumor microenvironment (TME) and a spontaneous murine model that faithfully recapitulates human disease. Methods: Histology and immunohistochemistry (IHC) staining was performed on human CCA and adjacent normal liver. Mice with targeted hepatic Kras activation and loss of p53 (KPPC) spontaneously develop CCA. KPPC hepatic tumors and normal livers from littermate controls underwent histological and gene expression studies. Flow cytometric analysis was performed on bone marrow, spleen, peripheral blood, CCA tumors and normal littermate livers. Results: Digital IHC quantification of archival human CCA specimens demonstrated elevated levels of CD15+CXCR2+ granulocytic myeloid derived suppressor cells (G-MDSC) compared to adjacent normal liver (p = < 0.05). In addition, the CXCR2 ligand, CXCL5, was significantly elevated in CCA tumors compared to adjacent normal liver. In KPPC mice, flow cytometric analysis of hepatic tumors showed an abundance of CD45+ leukocytes comprised of immunosuppressive G-MDSC vs normal littermate controls (p = 0.0007) which recapitulates human disease. qRT-PCR demonstrated significantly increased expression of G-csf, Csf1, Cxcl1, Cxcl2, and Cxcl5 (p = < 0.0001) in CCA KPPC tumors compared to normal livers. Accordingly, granulocytes in KPPC mice were elevated in both the bone marrow and blood compared to normal littermate controls. Conclusions: These data suggest CCA co-opts the ELR+ cytokine/CXCR2 axes to mobilize and recruit immunosuppressive G-MDSC to the TME. Targeted therapy against tumor infiltrating neutrophils can be tested in this pre-clinical model to inform clinical translation.

Mice with targeted KrasG12D and loss of p53 in the liver: A robust model for studying immunologic interventions for treating cholangiocarcinoma

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 281-281
Author(s):  
Booyeon Julia Han ◽  
Nathania Figueroa ◽  
Brian Belt ◽  
Michael O'Dell ◽  
Aram F. Hezel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Signaling Pathways ◽  
Immune Cell ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Suppressor Cells ◽  
Normal Liver ◽  
Liver Malignancy ◽  
Immune Signaling

281 Background: Inflammation in the tumor microenvironment—chronically elevated cytokines, chemokines, and inflammatory cells—promotes tumorigenesis. Cholangiocarcinoma (CC) is the most common liver malignancy within the biliary tree with few treatment options and a poor 5-year survival. CC tumors are characterized with a dense tumor stroma and abundant inflammatory immune cell infiltrate, yet little is known about the immune dynamics underlying the disease. Here, we characterize immune signaling pathways in human CC and a spontaneous mouse model of the disease to identify potential targets susceptible to immune based therapies. Methods: Histology and immunohistochemistry (IHC) were performed on archived human specimens and tissue microarrays of 52 CC specimens constructed under an IRB approved protocol to identify the prognostic significance of cytokine and immune markers. Peripheral blood, bone marrow, and tissue from mice with targeted activation of KrasG12D and loss of p53 (Kras-p53-/-) in the liver that spontaneously developed CC tumors versus normal controls were collected and analyzed by histology, IHC, quantitative gene expression, and flow cytometry based studies. Results: High levels of inflammatory leukocytes in human CC were predominantly of monocytic and granulocytic origin including macrophages (TAM) and granulocytic-myeloid derived suppressor cells (G-MDSC) respectively. Malignant cells expressed high levels of CCL2 and TAM stained positive for its cognate receptor CCR2. In addition, CD8+ and CD4+ T cells expressing PD-1 were associated with PD-L1+ tumor cells. Kras-p53-/- mice developed CC tumors histologically similar to human disease: tumors had high levels of cytokines and induced myelopoiesis leading to significantly more monocytes and granulocytes in the bone marrow, blood, and spleen compared to normal liver controls. Tumors also expressed higher levels of CCL2 and PD-L1 with more CCR2+ TAMs and PD-1+ T cells compared to controls. Conclusions: Human CC utilizes immune signaling pathways and Kras-p53-/- mice recapitulate the immune dynamics of the disease representing a model to study immune based therapies for treating CC.

scholarly journals Aberrant Ki-67 expression in normal bone marrow revealed by multiparameter flow cytometric analysis

Cytometry ◽  
1991 ◽  
Vol 12 (1) ◽  
pp. 50-63 ◽  
Author(s):  
Dirk R. Van Bockstaele ◽  
Jar Lan ◽  
Hans-W. Snoeck ◽  
Marcel L. Korthout ◽  
Robrecht F. De Bock ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometric Analysis ◽  
Normal Bone Marrow ◽  
Ki 67 ◽  
Normal Bone ◽  
Flow Cytometric

Flow Cytometric Analysis of Prostatic Carcinoma with and without Bone Marrow Metastasis

1992 ◽  
pp. 189-191
Author(s):  
Masakuni Furusato ◽  
William C. Allsbrook ◽  
Hiroyuki Kato ◽  
Hiroyuki Takahashi ◽  
Yuri Miyasaka ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prostatic Carcinoma ◽  
Flow Cytometric Analysis ◽  
Bone Marrow Metastasis ◽  
Flow Cytometric

scholarly journals Granulocytic Myeloid-Derived Suppressor Cells Aggravate Tuberculosis Caused by Hypervirulent Mycobacteria

2020 ◽  
Author(s):  
Caio César Barbosa Bomfim ◽  
Eduardo Pinheiro Amaral ◽  
Igor Santiago-Carvalho ◽  
Gislane Almeida Santos ◽  
Érika Machado Salles ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Function ◽  
Pulmonary Inflammation ◽  
Bacterial Load ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Partial Recovery ◽  
Myeloid Derived Suppressor Cells

Abstract Background The role of myeloid-derived suppressor cells (MDSCs) in severe tuberculosis patients who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. Methods This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. Results CD11b +GR1 int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b +GR1 int (Ly6G intLy6C int) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T cell suppression occurred concomitantly with CD11b +GR1 int cell accumulation in the lungs. Furthermore, lung and bone-marrow GR1 + cells suppressed both T cell proliferation and IFN-γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. Conclusions Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.

Immature myeloid Gr-1+ CD11b+ cells from lipopolysaccharide-immunosuppressed mice acquire inhibitory activity in the bone marrow and migrate to lymph nodes to exert their suppressive function

2016 ◽  
Vol 130 (4) ◽  
pp. 259-271 ◽  
Author(s):  
Veronica I. Landoni ◽  
Daiana Martire-Greco ◽  
Nahuel Rodriguez-Rodrigues ◽  
Paula Chiarella ◽  
Pablo Schierloh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Lymph Nodes ◽  
Inhibitory Activity ◽  
Suppressor Cells ◽  
T Cell Responses ◽  
Myeloid Derived Suppressor Cells ◽  
Suppressive Function ◽  
Cell Responses ◽  
Immunosuppressed Mice

LPS-induced immunosuppression, mimicking the state observed in patients with late sepsis, induced in bone marrow a population of myeloid-derived suppressor cells (Gr-1+ CD11b+) with the ability to inhibit T-cell responses and migrate to lymph nodes to exert their suppressive function.

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