Immature Immunosuppressive CD14+HLA-DR−/low Cells in Melanoma Patients Are Stat3hi and Overexpress CD80, CD83, and DC-Sign

Poschke, Isabel; Mougiakakos, Dimitrios; Hansson, Johan; Masucci, Giuseppe; Kiessling, Rolf

doi:10.1158/0008-5472.can-09-3767

Cited by 364 publications

(377 citation statements)

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“…In agreement with this evidence, our results revealed an upregulation of NADPH oxidase and p-STAT3 in splenic MDSCs from infected BALB/c mice. In fact STAT3 not only prevents apoptosis but is also a crucial regulator of MDSCs expansion [38][39][40].Many of the biological effects attributed to NO are actually mediated by peroxynitrites that are crucial mediators of MDSCsmediated suppression. These peroxynitrites induce the nitration of amino acids such as tyrosine, among others, and cause several alterations in T cells including the loss of TCR ζ-chain expression [2].…”

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confidence: 99%

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

et al. 2013

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Myeloid-derived suppressor cells (MDSCs Keywords: Inflammation r MDSCs r Nitric oxide r ROS r Trypanosoma cruziAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMyeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population consisting of immature macrophages, granulocytes, and dendritic cells as well as myeloid progenitor cells. They are considered to be one of the major components of the immune suppressive network responsible for suppressing T-cell responses in pathological conditions [1,2] as well as in the regulation of the immune response in healthy individuals [3]. These Correspondence: Dr. Susana Gea e-mail: sgea@fcq.unc.edu.ar myeloid cells are commonly identified in mice by the co-expression of the surface markers CD11b and Gr1 (Ly6G/Ly6C) and have been divided into two subsets: granulocytic (G) MDSCs with a CD11b + LY6G + LY6C low phenotype and monocytic (M) MDSCs with CD11b + LY6G − LY6C high phenotype [3,4]. Despite their morphological similarities, G-MDSCs and neutrophils are functionally and phenotypically different. G-MDSCs, but not neutrophils, are immunosuppressive and express higher levels of arginase-1 and myeloperoxidase than neutrophils, and also have increased production of reactive oxygen species (ROS) [5,6]. Although * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2014. 44: 184-194 Immunomodulation 185 M-MDSCs and inflammatory monocytes share the same phenotype and morphology, these cells are functionally distinct since M-MDSCs are highly immunosuppressive and they express high levels of both iNOS and arginase-1. Furthermore, although iNOS expression is a hallmark of a tumoricidal/microbicidal phenotype in M1 macrophages, iNOS promotes suppressive activities in M-MDSCs. This shift in iNOS activity most likely reflects the crosstalk of iNOS with other enzymes such as NADPH oxidase to promote the production of peroxynitrites, which inhibits the proliferation and effector function of T cells [2]. MDSCs use several mechanisms in addition to the production of ROS and NO, such as triggering apoptosis of activated T cells by depleting of L-arginine, via arginase [7][8][9][10]. There is also evidence that MDSCs may suppress immune activation by inducing T regulatory cell expansion [11]. Other suppressive mechanisms that have recently been proposed include the production of TGF-β [12,13], depletion of cysteine [8], induction of COX2 and prostaglandin E2 [1,[14][15][16].Trypanosoma cruzi an obligate intracellular protozoan, is the causative agent of Chagas disease. This disease affects about 20 million people in Latin America, with 120 million persons at risk. In the past decades, mainly as a result of increased migrations, the diagnosed cases have also increased in nonendemic countries such as Canada, United States of America, and Europe. This has led to an increased risk of transmission of the infection, mainly through blood transfusion and organ transplantation [17]. Pa...

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Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

et al. 2013

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“…HLA-DR loss on CD14 C monocytes has been shown to be a major event in tumor-induced immunosuppression. [11][12][13][14][15][16][17][18] We have shown in our results that this population of immunosuppressive monocytes is elevated in PC in terms of the percentage of total monocytes and in cell count (data not shown) ( Fig. 2A, left panel).…”

Section: Immunophenotypic Changes In Pc Patientsmentioning

confidence: 56%

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

et al. 2016

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Immunological strategies to treat pancreatic cancer offer new therapeutic approaches to improve patient outcomes. Understanding alterations in the immune systems of pancreatic cancer patients will likely lead to advances in immunotherapy for the disease. We profiled peripheral blood leukocytes from pancreatic cancer patients (n D 22) and age-matched controls (n D 20) using flow cytometry. Immune profiling of pancreatic cancer patients identified phenotypic changes in various immune cell populations, including a population of immunosuppressive monocytes (CD14 C HLA-DR lo/neg ), which were shown to be increased in these patients. There was a correlation between the levels of CD14 C monocytes and the levels of CD14 C HLA-DR lo/neg monocytes in peripheral blood from pancreatic cancer patients. HLA-DR downregulation of monocytes was shown to occur through pancreatic cancer-derived exosome interactions with monocytes. In an in vitro model, exosomes from patient-derived xenograft cell lines and patient plasma decreased HLA-DR expression on CD14 C monocytes. Additionally, tumor-derived exosomes caused immune suppression in monocytes through altered STAT3 signaling, induction of arginase expression, and reactive oxygen species. These findings provide novel insights into the mechanisms that govern immunosuppression in pancreatic cancer. Understanding monocyte-exosome interactions could lead to novel immunotherapies for this disease.

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“…MDSCs were characterized by the CD14 þ CD11b þ HLA-DR À/low phenotype (24)(25)(26)(27)(28) and NK cells as CD16 þ CD56 low (29). PBMCs were stained with CD3/PerCP, CD4/PerCP, CD8/PerCP, HLA-DR/PerCP-Cy5.5, CD11b/APC-Cy7 (BD Biosciences), CD56/Alexa Fluor 700 (BD Pharmingen), CD14/Pe-Cy7, and CD16/Pacific Blue (BioLegend).…”

Section: Analysis Of Immune Cell Subsetsmentioning

confidence: 99%

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

Weide¹,

Eigentler²,

Pflugfelder³

et al. 2014

Cancer Immunology Research

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L19-IL2 is a recombinant protein comprising the cytokine IL2 fused to the single-chain monoclonal antibody L19. In previous studies, intralesional injection with IL2 has shown efficacy for the locoregional treatment of cutaneous/subcutaneous metastases in patients with advanced melanoma. The objectives of this study were to investigate whether (i) intralesional delivery of a targeted form of IL2 would yield similar results, with reduction of injection frequency and treatment duration; and (ii) systemic immune responses were induced by the local treatment. Patients with stage IIIB/IIIC melanoma and cutaneous/subcutaneous injectable metastases received weekly intratumoral injections of L19-IL2 at a maximum dose of 10 MIU/week for 4 consecutive weeks. Tumor response was evaluated 12 weeks after the first treatment. Twenty-four of 25 patients were evaluable for therapyinduced responses. A complete response (CR) by modified immune-related response criteria (irRC) of all treated metastases was achieved in 6 patients (25%), with long-lasting responses in most cases (5 patients for !24 months). Objective responses were documented in 53.9% of all index lesions [44.4% CR and 9.5% partial responses (by irRC)], and 36.5% of these remained stable, while 9.5% progressed. Toxicity was comparable with that of free IL2, and no serious adverse events were recorded. A significant temporary increase of peripheral regulatory T cells and natural killer cells, sustained increase of absolute CD4 þ lymphocytes, and decrease of myeloid-derived suppressor cells were observed upon treatment. Finally, we recorded encouraging data about the progression time to distant metastases and overall survival. Cancer Immunol Res; 2(7); 668-78. Ó2014 AACR.

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Immature Immunosuppressive CD14+HLA-DR−/low Cells in Melanoma Patients Are Stat3hi and Overexpress CD80, CD83, and DC-Sign

Cited by 364 publications

References 46 publications

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

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Immature Immunosuppressive CD14+HLA-DR−/low Cells in Melanoma Patients Are Stat3hi and Overexpress CD80, CD83, and DC-Sign

Cited by 364 publications

References 46 publications

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

Myeloid‐derived suppressor cells are key players in the resolution of inflammation during a model of acute infection

Immunosuppressive CD14+HLA-DRlo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

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Immunosuppressive CD14⁺HLA-DR^lo/negmonocytes are elevated in pancreatic cancer and “primed” by tumor-derived exosomes