Monocytic CCR2+ Myeloid-Derived Suppressor Cells Promote Immune Escape by Limiting Activated CD8 T-cell Infiltration into the Tumor Microenvironment

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2012-02, Vol.72 (4), p.876-886
Main Authors: LESOKHIN, Alexander M, HOHL, Tobias M, MERGHOUB, Taha, WOLCHOK, Jedd D, KITANO, Shigehisa, CORTEZ, Czrina, HIRSCHHORN-CYMERMAN, Daniel, AVOGADRI, Francesca, RIZZUTO, Gabrielle A, LAZARUS, John J, PAME, Eric G, HOUGHTON, Alan N
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
CD11b Antigen - metabolism
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Female
Granulocyte-Macrophage Colony-Stimulating Factor
Immune Tolerance - immunology
Lymphocyte Activation
Medical sciences
Melanoma - immunology
Melanoma, Experimental - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myeloid Cells - immunology
Myeloid Cells - metabolism
Pharmacology. Drug treatments
Receptors, CCR2 - metabolism
Tumor Escape - immunology
Tumor Microenvironment - immunology
Tumors
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Summary:Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of cytotoxic antitumor T effector cells. Heterogeneity in these cells poses a significant barrier to studying the in vivo contributions of individual MDSC subtypes. Herein, we show that granulocyte-macrophage colony stimulating factor, a cytokine critical for the numeric and functional development of MDSC populations, promotes expansion of a monocyte-derived MDSC population characterized by expression of CD11b and the chemokine receptor CCR2. Using a toxin-mediated ablation strategy to target CCR2-expressing cells, we show that these monocytic MDSCs regulate entry of activated CD8 T cells into the tumor site, thereby limiting the efficacy of immunotherapy. Our results argue that therapeutic targeting of monocytic MDSCs would enhance outcomes in immunotherapy.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-11-1792