Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer

Nefedova, Yulia; Huang, Mei; Kusmartsev, Sergei; Bhattacharya, Raka; Cheng, Pingyan; Salup, Raoul; Jove, Richard; Gabrilovich, Dmitry I.

doi:10.4049/jimmunol.172.1.464

Cited by 406 publications

(323 citation statements)

References 30 publications

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“…Previous studies implicated STAT6 as possible factor involved in immune suppression associated with myeloid cells (14,41,42). We have demonstrated important role of STAT3 in accumulation of Gr-1 ϩ IMC in cancer (13), and a number of groups demonstrated important role of STAT1 in regulation of iNOS activity (43,44). Present study demonstrated that increased STAT6 activity in TAM was not responsible for their immunosuppressive activity.…”

Section: Figurementioning

confidence: 55%

“…Hyperactivation of Jak2-STAT3 pathway was recently implicated in abnormal myeloid cell differentiation and function in cancer (13,32). Elevated level of STAT3 activity was observed in different myeloid cells isolated from tumor-bearing mice (13).…”

Section: Role Of Stat Transcription Factors In Tam-mediated T Cell Inmentioning

confidence: 99%

“…IMC are present in bone marrow and spleens of healthy mice, and under normal conditions differentiate into mature myeloid cells (12). However, they accumulate in large numbers in tumor-bearing mice probably due to the effect of various tumor-derived factors (13)(14)(15)(16)(17)(18). Gr-1 ϩ IMC freshly isolated from spleen of tumor-bearing mice could not inhibit CD4-mediated T cell response, but were able to suppress CD8 ϩ T cells in Ag-dependent manner (16).…”

Section: Stat1 Signaling Regulates Tumor-associated Macrophage-mediatmentioning

confidence: 99%

“…Elevated level of STAT3 activity was observed in different myeloid cells isolated from tumor-bearing mice (13). We evaluated the level of STAT3 activation in F4/80 ϩ cells isolated from control and tumor-bearing mice.…”

Section: Role Of Stat Transcription Factors In Tam-mediated T Cell Inmentioning

confidence: 99%

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STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Kusmartsev

Gabrilovich

2005

The Journal of Immunology

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It is well established that tumor progression is associated with the accumulation of myeloid suppressive cells, which in mice include Gr-1+ immature myeloid cells and F4/80+ macrophages. The paradox is that with the exception of terminal stages of the disease or chemotherapy treatment, tumor-bearing mice or cancer patients do not display a profound systemic immune suppression. We therefore raised the question as to whether myeloid cell-mediated T cell suppression is controlled at a local level at the site of the tumor. We have demonstrated that after adoptive transfer to tumor-bearing recipients, Gr-1+ (immature myeloid cells) freshly isolated from spleens of tumor-bearing mice become F4/80+ tumor-associated macrophages (TAM). These TAM, but not F4/80+ macrophages or Gr-1+ cells freshly isolated from spleens of tumor-bearing or naive mice were able to inhibit T cell-mediated immune response in vitro via induction of T cell apoptosis. Arginase and NO were both responsible for the apoptotic mechanism, and were seen only in TAM, but not in freshly isolated Gr1+ cells. Using the analysis of STAT activity in combination with STAT knockout mice, we have determined that STAT1, but not STAT3 or STAT6, was responsible for TAM-suppressive activity.

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Section: Figurementioning

confidence: 55%

Section: Role Of Stat Transcription Factors In Tam-mediated T Cell Inmentioning

confidence: 99%

Section: Stat1 Signaling Regulates Tumor-associated Macrophage-mediatmentioning

confidence: 99%

Section: Role Of Stat Transcription Factors In Tam-mediated T Cell Inmentioning

confidence: 99%

See 2 more Smart Citations

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Kusmartsev

Gabrilovich

2005

The Journal of Immunology

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389

325

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“…Leptin activates the JAK-STAT signaling pathway, and an optimal level of STAT3 activation is critically important for normal DC differentiation [19]. With Western blot analysis of sorting-purified viable splenic CD11c + MHC-II + immature DC and LPS-matured DC, phosphorylated STAT3 was shown to be markedly reduced in immature db/db DC, whereas a moderate reduction was observed in mature db/db DC (Fig.…”

Section: Impaired Signaling Pathways In Db/db DCmentioning

confidence: 95%

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

et al. 2006

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Previous studies demonstrated that lymphocyte development is impaired in leptin receptor (Ob-R)-deficient db/db mice. However, it remains unclear whether or not leptin signaling plays a physiological role in dendritic cell (DC) development and function. In this study, we first detected Ob-R expression in murine DC. Using db/db mice at a pre-diabetic stage, we demonstrate that the total number of DC generated from bone marrow (BM) cultures is significantly lower than in WT controls. Similarly, selective blockade of leptin with a soluble mouse Ob-R chimera (Ob-R:Fc) inhibited DC generation in wild-type BM cultures. The reduced DC yield in db/db BM culture was attributed to significantly increased apoptosis, which was associated with dysregulated expression of Bcl-2 family genes. Moreover, db/db DC displayed markedly reduced expression of co-stimulatory molecules and a Th2-type cytokine profile, with a poor capacity to stimulate allogeneic T cell proliferation. Consistent with their impaired DC phenotype and function, db/db DC showed significantly down-regulated activities of the PI3K/Akt pathway as well as STAT-3 and IjB-a. In conclusion, our findings demonstrate the involvement of leptin signaling in DC survival and maturation.See accompanying commentary: http://dx

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Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma

Celis

2007

Cancer

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BACKGROUND. MPS160 (GRAMLGTHTMEVTV) is a glycoprotein 100‐derived melanoma peptide that contains overlapping human leukemic antigen A2‐, DR53‐, and DQw6‐restricted T‐cell epitopes. In preclinical testing, MPS160 demonstrated superior immunization and antitumor activity. In this report, the authors present the results from a clinical trial that evaluated the safety and immunologic efficacy of the MPS160 vaccine in patients with metastatic melanoma. METHODS. Patients with stage IV melanoma were randomized to 1 of 3 treatment arms: 1) MPS160 in incomplete Freund adjuvant (Montanide ISA‐51); 2) MPS160 in Montanide ISA‐51 with 75 μg of granulocyte‐macrophage–stimulating factor (GM‐CSF); or 3) MPS160 in Montanide ISA‐51 with 100 μg of GM‐CSF. Vaccines were administered every 3 weeks until patients developed disease progression or severe toxicity. Patients were aged ≥18 years with metastatic melanoma and a good performance status. Exclusion criteria included pregnancy/nursing, brain metastases, and ongoing chemotherapy. Immunologic efficacy was ascertained by using tetramer and functional analysis of peripheral blood lymphocytes. RESULTS. None of the 28 patients exhibited objective tumor responses or severe toxicities. Four patients remained progression free for ≥100 days. Immunologic analysis was available for 21 patients. Laboratory data demonstrated 1) increased frequency of vaccine‐specific, nonfunctional cytotoxic T lymphocytes in 10 patients; 2) no differences in immunization efficacy among the treatment arms; and 3) evidence of systemic cytokine/immune dysfunction. CONCLUSIONS. Clinically, the MPS160 vaccine was ineffective. Phenotypic (tetramer) evidence of immunization was ineffective functionally and most likely was caused by global immune dysfunction, as illustrated by abnormal cytokine profiles in peripheral blood. In this report, the authors discuss possible implications of the current results on future cancer vaccine studies. Cancer 2007. © 2007 American Cancer Society.

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Hyperactivation of STAT3 Is Involved in Abnormal Differentiation of Dendritic Cells in Cancer

Cited by 406 publications

References 30 publications

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

STAT1 Signaling Regulates Tumor-Associated Macrophage-Mediated T Cell Deletion

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

Overlapping human leukocyte antigen class I/II binding peptide vaccine for the treatment of patients with stage IV melanoma

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