title: Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment.
abstract: 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.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Lesokhin
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Hohl
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.forename: Czrina
authors.initials: C
authors.lastname: Cortez
authors.forename: Daniel
authors.initials: D
authors.lastname: Hirschhorn-Cymerman
authors.forename: Francesca
authors.initials: F
authors.lastname: Avogadri
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Rizzuto
authors.forename: John J
authors.initials: JJ
authors.lastname: Lazarus
authors.forename: Eric G
authors.initials: EG
authors.lastname: Pamer
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism*; D019139:Tumor Escape / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor