Journal Article
. 2010 Feb; 184(6):3106-16.
doi: 10.4049/jimmunol.0902661.

Mechanism of T cell tolerance induced by myeloid-derived suppressor cells

Srinivas Nagaraj 1 Adam G Schrum  Hyun-Il Cho  Esteban Celis  Dmitry I Gabrilovich  
  • PMID: 20142361
  •     38 References
  •     182 citations


Ag-specific T cell tolerance plays a critical role in tumor escape. Recent studies implicated myeloid-derived suppressor cells (MDSCs) in the induction of CD8(+) T cell tolerance in tumor-bearing hosts. However, the mechanism of this phenomenon remained unclear. We have found that incubation of Ag-specific CD8(+) T cells, with peptide-loaded MDSCs, did not induce signaling downstream of TCR. However, it prevented subsequent signaling from peptide-loaded dendritic cells. Using double TCR transgenic CD8(+) T cells, we have demonstrated that MDSC induced tolerance to only the peptide, which was presented by MDSCs. T cell response to the peptide specific to the other TCR was not affected. Incubation of MDSCs with Ag-specific CD8(+) T cells caused nitration of the molecules on the surface of CD8(+) T cells, localized to the site of physical interaction between MDSC and T cells, which involves preferentially only TCR specific for the peptide presented by MDSCs. Postincubation with MDSCs, only nitrotyrosine-positive CD8(+) T cells demonstrated profound nonresponsiveness to the specific peptide, whereas nitrotyrosine-negative CD8(+) T cells responded normally to that stimulation. MDSCs caused dissociation between TCR and CD3zeta molecules, disrupting TCR complexes on T cells. Thus, these data describe a novel mechanism of Ag-specific CD8(+) T cell tolerance in cancer.

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Front Immunol, 2015 Nov 04; 6. PMID: 26528286    Free PMC article.
The prognostic effects of tumor infiltrating regulatory T cells and myeloid derived suppressor cells assessed by multicolor flow cytometry in gastric cancer patients.
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Oncotarget, 2016 Jan 23; 7(7). PMID: 26799288    Free PMC article.
Neutrophils in Cancer: Two Sides of the Same Coin.
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J Immunol Res, 2016 Jan 29; 2015. PMID: 26819959    Free PMC article.
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Hepatitis C Virus-Induced Myeloid-Derived Suppressor Cells Suppress NK Cell IFN-γ Production by Altering Cellular Metabolism via Arginase-1.
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J Immunol, 2016 Jan 31; 196(5). PMID: 26826241    Free PMC article.
The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.
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Trends Immunol, 2016 Feb 10; 37(3). PMID: 26858199    Free PMC article.
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Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors.
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Oncotarget, 2016 Mar 05; 7(17). PMID: 26943036    Free PMC article.
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Mediators Inflamm, 2016 Mar 12; 2016. PMID: 26966341    Free PMC article.
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Granulocyte-like myeloid derived suppressor cells (G-MDSC) are increased in multiple myeloma and are driven by dysfunctional mesenchymal stem cells (MSC).
Cesarina Giallongo, Daniele Tibullo, +10 authors, Francesco Di Raimondo.
Oncotarget, 2016 Mar 12; 7(52). PMID: 26967390    Free PMC article.
Signal transducer and activator of transcription 3 in myeloid-derived suppressor cells: an opportunity for cancer therapy.
Inès Dufait, Els Van Valckenborgh, +3 authors, Karine Breckpot.
Oncotarget, 2016 Mar 31; 7(27). PMID: 27029037    Free PMC article.
Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.
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Lancet Oncol, 2016 Apr 09; 17(5). PMID: 27055731    Free PMC article.
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Joshua L Hood.
Med Hypotheses, 2016 Apr 12; 90. PMID: 27063077    Free PMC article.
Myeloid-Derived Suppressor Cells in Bacterial Infections.
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Front Cell Infect Microbiol, 2016 Apr 12; 6. PMID: 27066459    Free PMC article.
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Toxicol Appl Pharmacol, 2016 May 11; 304. PMID: 27163765    Free PMC article.
Overcoming barriers to effective immunotherapy: MDSCs, TAMs, and Tregs as mediators of the immunosuppressive microenvironment in head and neck cancer.
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Oral Oncol, 2016 May 25; 58. PMID: 27215705    Free PMC article.
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Sci Rep, 2016 Jun 04; 6. PMID: 27256519    Free PMC article.
The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications.
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Ann Transl Med, 2016 Jun 09; 4(9). PMID: 27275486    Free PMC article.
Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards.
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Nat Commun, 2016 Jul 07; 7. PMID: 27381735    Free PMC article.
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Mesenchymal Stem Cells (MSC) Regulate Activation of Granulocyte-Like Myeloid Derived Suppressor Cells (G-MDSC) in Chronic Myeloid Leukemia Patients.
Cesarina Giallongo, Alessandra Romano, +9 authors, Francesco Di Raimondo.
PLoS One, 2016 Jul 09; 11(7). PMID: 27391078    Free PMC article.
Induction of Suppressor Cells and Increased Tumor Growth following Chronic Psychosocial Stress in Male Mice.
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PLoS One, 2016 Jul 09; 11(7). PMID: 27391954    Free PMC article.
Melanoma exosome induction of endothelial cell GM-CSF in pre-metastatic lymph nodes may result in different M1 and M2 macrophage mediated angiogenic processes.
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Med Hypotheses, 2016 Aug 16; 94. PMID: 27515216    Free PMC article.
Monitoring of the Immune Dysfunction in Cancer Patients.
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Vaccines (Basel), 2016 Sep 07; 4(3). PMID: 27598210    Free PMC article.
Sunitinib: the antiangiogenic effects and beyond.
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Onco Targets Ther, 2016 Sep 24; 9. PMID: 27660467    Free PMC article.
Immature myeloid cells in the tumor microenvironment: Implications for immunotherapy.
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Clin Immunol, 2016 Nov 04; 189. PMID: 27777083    Free PMC article.
One microenvironment does not fit all: heterogeneity beyond cancer cells.
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Cancer Metastasis Rev, 2016 Nov 20; 35(4). PMID: 27858305    Free PMC article.
Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone.
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Front Immunol, 2016 Dec 21; 7. PMID: 27994586    Free PMC article.
IL-6 Improves the Nitric Oxide-Induced Cytotoxic CD8+ T Cell Dysfunction in Human Chagas Disease.
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Front Immunol, 2017 Jan 10; 7. PMID: 28066435    Free PMC article.
Transcriptional Profiling in Experimental Visceral Leishmaniasis Reveals a Broad Splenic Inflammatory Environment that Conditions Macrophages toward a Disease-Promoting Phenotype.
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PLoS Pathog, 2017 Feb 01; 13(1). PMID: 28141856    Free PMC article.
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Oncotarget, 2017 May 04; 8(16). PMID: 28460461    Free PMC article.
Phenotype and Function of Myeloid-Derived Suppressor Cells Induced by Porphyromonas gingivalis Infection.
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Infect Immun, 2017 May 24; 85(8). PMID: 28533469    Free PMC article.
Granulocytic myeloid-derived suppressor cells suppress virus-specific CD8+ T cell responses during acute Friend retrovirus infection.
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Retrovirology, 2017 Aug 25; 14(1). PMID: 28835242    Free PMC article.
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Int J Clin Oncol, 2017 Nov 01; 23(2). PMID: 29086877
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Sci Rep, 2017 Nov 15; 7(1). PMID: 29133913    Free PMC article.
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Oncotarget, 2017 Nov 16; 8(47). PMID: 29137227    Free PMC article.
Monocytic myeloid-derived suppressor cells as prognostic factor in chronic myeloid leukaemia patients treated with dasatinib.
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J Cell Mol Med, 2017 Dec 09; 22(2). PMID: 29218828    Free PMC article.
Toll-like receptor 2 ligand and interferon-γ suppress anti-tumor T cell responses by enhancing the immunosuppressive activity of monocytic myeloid-derived suppressor cells.
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Oncoimmunology, 2018 Jan 04; 7(1). PMID: 29296526    Free PMC article.
Loss of Muscle Mass is a Novel Predictor of Postoperative Early Recurrence in N2-Positive Non-Small-Cell Lung Cancer.
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Ann Thorac Cardiovasc Surg, 2018 Feb 21; 24(3). PMID: 29459570    Free PMC article.
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Front Physiol, 2018 Mar 09; 9. PMID: 29515456    Free PMC article.
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Med Sci (Basel), 2018 Mar 09; 6(1). PMID: 29517999    Free PMC article.
The Impact of Radiation on the Tumor Microenvironment: Effect of Dose and Fractionation Schedules.
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Cancer Growth Metastasis, 2018 Mar 20; 11. PMID: 29551910    Free PMC article.
Under-Evaluated or Unassessed Pathogenic Pathways in Autoimmune Hepatitis and Implications for Future Management.
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Dig Dis Sci, 2018 Apr 20; 63(7). PMID: 29671161
Validation of Different Nutritional Assessment Tools in Predicting Prognosis of Patients with Soft Tissue Spindle-Cell Sarcomas.
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Nutrients, 2018 Jun 15; 10(6). PMID: 29899304    Free PMC article.
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Mol Cancer, 2018 Jun 16; 17(1). PMID: 29903049    Free PMC article.
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Gen Thorac Cardiovasc Surg, 2018 Aug 15; 66(12). PMID: 30105630
Recruitment of CCR2+ tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer.
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Oncoimmunology, 2018 Sep 20; 7(9). PMID: 30228938    Free PMC article.
Hematopoietic stem cell specific V-ATPase controls breast cancer progression and metastasis via cytotoxic T cells.
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Oncotarget, 2018 Sep 22; 9(69). PMID: 30237863    Free PMC article.
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JCI Insight, 2019 Sep 04; 4(18). PMID: 31479429    Free PMC article.
Pretreatment Inflammatory Indexes as Prognostic Predictors of Survival in Patients Suffering From Synovial Sarcoma.
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Brain Behav Immun, 2019 Dec 01; 84. PMID: 31785394    Free PMC article.
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Novel Combinatorial Approaches to Tackle the Immunosuppressive Microenvironment of Prostate Cancer.
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Immune-Related Gene SERPINE1 Is a Novel Biomarker for Diffuse Lower-Grade Gliomas via Large-Scale Analysis.
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Preoperative Immunotherapy in the Multidisciplinary Management of Oral Cavity Cancer.
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Receptor Tyrosine Kinase Inhibitor Sunitinib as Novel Immunotherapy to Inhibit Myeloid-Derived Suppressor Cells for Treatment of Endometriosis.
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