Stimulation of immune suppressive CD34 + cells from normal bone marrow by Lewis lung carcinoma tumors

Wright, M. A.; Wiers, Kristina; Vellody, K.; Djordjević, Dejan; Young, Matthew R.

doi:10.1007/s002620050485

Cited by 18 publications

(21 citation statements)

References 33 publications

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Section: Introductionmentioning

confidence: 99%

“…30 Granulocyte macrophage-colony-stimulating factor (GM-CSF) secretion has correlated with the capacity of tumor metastases and the GM-CSF and IL-3 in conditioned medium from Lewis lung carcinoma may induce MDSCs from bone marrow culture. 31 The concentration of GM-CSF plays a critical role in the balancing act between immune suppression by MDSCs and immune activation by mature dendritic cells. 7 Additional evidence suggests that many cytokines, such as tumor necrosis factor ␣ (TNF-␣), GM-CSF, interferon ␥ (IFN-␥), IL-6, IL-4, VEGF, transforming growth factor ␤ (TGF-␤), IL-10, and Flt3 ligand are likely to be involved in the differentiation of myeloid progenitors present in blood, bone marrow, and spleen.…”

Section: Introductionmentioning

confidence: 99%

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Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Pan

Wang²,

Yin³

et al. 2008

Blood

288

224

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IntroductionImmune-based therapy has achieved a certain level of success; however, the overall therapeutic effect has been much less promising due to the immune suppressive mechanisms associated with advanced malignancies. 1 To achieve a better therapeutic efficacy of immune activation therapy, the mechanism or mechanisms by which a large tumor burden prevents immune activation from inducing effective antitumor immunity needs to be elucidated.Tumor growth is accompanied by an increase in the number of Gr-1 ϩ Mac-1 ϩ myeloid-derived suppressor cells (MDSCs) 2-4 and tumor-specific T regulatory cells (Tregs) 5,6 with strong immune suppressive activity in cancer patients and in tumor-bearing mice. [7][8][9] Both MDSCs and Tregs may be directly involved in immune unresponsiveness in active immune therapy.It has been demonstrated that MDSCs are involved in T-cell hyporesponsiveness in tumor-bearing mice. Several mechanisms by which MDSCs regulate the tumor-specific T-cell response have recently been proposed and the in vivo immune regulatory effects of MDSCs on tumor-specific T-cell response have been identified. 7-12 T-cell inactivation can be mediated by MDSCs through IFN␥-dependent nitric oxide (NO) production [12][13][14][15][16] or the Th2-mediated IL-4/IL-13-dependent arginase 1 pathway. 14,[17][18][19][20][21][22] In addition, a mechanism of ROS-mediated cell killing has been proposed. 3,23,24 Furthermore, MDSCs can inhibit cytotoxic T lymphocyte (CTL) responses through NOdependent or -independent mechanisms. Cell-to-cell contact appeared to be crucial in these mechanisms. 25 Our laboratory has further identified a novel mechanism of MDSC-mediated immune suppression on activated T cells through the development of Foxp3 ϩ T regulatory cells (Tregs) and T-cell tolerance both in vitro and in tumor-bearing mice. The induction of Tregs by MDSCs requires IFN-␥ and IL-10 but is independent of the NO-mediated suppressive mechanism. 11 To overcome MDSCmediated immune suppression and prevent Treg induction, it is critical to identify the tumor factors that are required for MDSC accumulation in tumor-bearing animals.Several lines of evidence support the hypothesis that the development and expansion of MDSCs may be modulated by tumor-secreted factors. MDSCs in tumor-bearing animals can differentiate into mature dendritic cells or remain as MDSCs with inhibitory activities, depending on the local cytokine milieu. 26,27 Human renal cell carcinoma cell lines release soluble factors (IL-6, M-CSF) that inhibit the differentiation of CD34 ϩ cells into dendritic cells (DCs) and trigger their commitment toward monocytic cells. 28 In a transgenic mammary tumor, VEGF levels correlate with the MDSC number. 29 Moreover, the in vivo infusion of vascular endothelial growth factor (VEGF) can induce MDSC development in naive mice and impair DC function and differentiation. 30 Granulocyte macrophage-colony-stimulating factor (GM-CSF) secretion has correlated with the capacity of tumor metastases and the GM-CSF and IL-3 in conditioned mediu...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Pan

Wang²,

Yin³

et al. 2008

Blood

288

224

View full text Add to dashboard Cite

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“…16,20,25 Our prior studies had shown the mobilization of CD34 1 progenitor cells into the peripheral blood of patients and animals whose tumors produce GM-CSF. 7,11,26 These include HNSCC and the murine LLC model. We had also previously shown the feasibility of using cytokine-containing implants for cell recruitment to the site of tumor excision.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10] Our studies have shown that these immune inhibitory CD34 1 cells are mobilized by tumor secretion of GM-CSF and that they are present in increased numbers in mice bearing Lewis lung carcinoma (LLC) tumors and in patients with head and neck squamous cell carcinomas. 7,11 They are also present within the cancer mass. Studies to determine the mechanisms that lead to their appearance within the tumor tissue showed that they can be chemoattracted by tumor-derived soluble products, with almost all of the chemotactic activity being attributable to VEGF.…”

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confidence: 99%

Cytokine‐containing gelfoam implants at a postsurgical tumor excision site to stimulate local immune reactivity

Young

2006

Intl Journal of Cancer

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We previously demonstrated increased numbers of CD34+ progenitor cells in the peripheral blood of tumor bearers. Also demonstrated was the feasibility of chemoattracting these cells by sponge implants containing VEGF. The present study used a murine Lewis lung carcinoma (LLC) model to test if CD34+ cells that are chemoattracted to a tumor excision site can be differentiated in situ into dendritic cells and whether this leads to increased local immune reactivity. After surgically excising established LLC tumors, mice received at the excision site gelatin sponge implants containing VEGF to chemoattract CD34+ cells, and/or GM‐CSF plus SCF to induce CD34+ cell differentiation into dendritic cells. In some studies, lysates of GFP‐transfected LLC cells (LLCGFP) were also included in the implants as a source of tumor antigen. After 2 weeks, implants and local lymph nodes were removed and analyzed. Implants containing VEGF, GM‐CSF/SCF or VEGF/GM‐CSF/SCF had a higher proportion of CD34+ cells compared to control implants. However, the number of dendritic cells was higher in implants containing GM‐CSF/SCF or VEGF/GM‐CSF/SCF than those containing either VEGF or diluent. Regional lymph node from mice containing GM‐CSF/SCF or VEGF/GM‐CSF/SCF implants showed increased dendritic cell levels. However, when lysates from LLCGFP were added to the implants, the highest proportion of dendritic cells associated with GFP was in lymph nodes of mice containing GM‐CSF/SCF implants. Lymph node cells from mice with GM‐CSF/SCF or VEGF/GM‐CSF/SCF had a higher level of proliferation and IFN‐γ secretion in response to in vitro LLC lysate challenge, with the greatest response being from lymph node cells of mice with GM‐CSF/SCF implants. These results suggest the feasibility of using GM‐CSF/SCF‐containing implants to increase dendritic cell levels, uptake of tumor antigens, trafficking to lymph nodes and stimulation of immune reactivity at tumor excision sites with residual tumor. © 2006 Wiley‐Liss, Inc.

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“…Earlier studies have described the presence of natural suppressors of lymphoproliferative responses with myeloid-cell characteristics in mice and humans (18)(19)(20)(21)(22). The finding that suppressive monocytes expressing CD11b/Mac-1 accumulate in the spleens of tumor-bearing mice (23), has led to the identification of T cell suppressors that express CD11b/Mac-1 and Gr-1 antigens in the spleens of mice immunized with highly immunogenic recombinant anti-cancer vaccines and tumor-bearing mice (24)(25)(26)(27) The fact that MDSC immune suppression can be reversed in vitro and in vivo has led to the development of a multitude of strategies in cancer therapy.…”

Section: Dedicationmentioning

confidence: 99%

Immunomodulation of myeloid-derived suppressor cells by particulate b-glucan in cancer.

Albeituni¹

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Stimulation of immune suppressive CD34 + cells from normal bone marrow by Lewis lung carcinoma tumors

Cited by 18 publications

References 33 publications

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function

Cytokine‐containing gelfoam implants at a postsurgical tumor excision site to stimulate local immune reactivity

Immunomodulation of myeloid-derived suppressor cells by particulate b-glucan in cancer.

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