title: Tumor-associated myeloid cells can be activated in vitro and in vivo to mediate antitumor effects.
abstract: Tumor growth is often accompanied by the accumulation of myeloid cells in the tumors and lymphoid organs. These cells can suppress T cell immunity, thereby posing an obstacle to T cell-targeted cancer immunotherapy. In this study, we tested the possibility of activating tumor-associated myeloid cells to mediate antitumor effects. Using the peritoneal model of B16 melanoma, we show that peritoneal cells (PEC) in tumor-bearing mice (TBM) had reduced ability to secrete nitric oxide (NO) following in vitro stimulation with interferon gamma and lipopolysaccharide, as compared to PEC from control mice. This reduced function of PEC was accompanied by the influx of CD11b(+) Gr-1(+) myeloid cells to the peritoneal cavity. Nonadherent PEC were responsible for most of the NO production in TBM, whereas in naïve mice NO was mainly secreted by adherent CD11b(+) F4/80(+) macrophages. Sorted CD11b(+) Gr-1(-) monocytic and CD11b(+) Gr-1(+) granulocytic PEC from TBM had a reduced ability to secrete NO following in vitro stimulation (compared to naïve PEC), but effectively suppressed proliferation of tumor cells in vitro. In vivo, treatment of mice bearing established peritoneal B16 tumors with anti-CD40 and CpG resulted in activation of tumor-associated PEC, reduction in local tumor burden and prolongation of mouse survival. Inhibition of NO did not abrogate the antitumor effects of stimulated myeloid cells. Taken together, the results indicate that in tumor-bearing hosts, tumor-associated myeloid cells can be activated to mediate antitumor effects.
authors.affiliation: Department of Human Oncology, University of Wisconsin, 4136 WIMR, 1111 Highland Avenue, Madison, WI 53705, USA. rakhmil@humonc.wisc.edu
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Rakhmilevich
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Baldeshwiler
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Van De Voort
authors.forename: Mildred A R
authors.initials: MA
authors.lastname: Felder
authors.forename: Richard K
authors.initials: RK
authors.lastname: Yang
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Kalogriopoulos
authors.forename: David S
authors.initials: DS
authors.lastname: Koslov
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D018899:CpG Islands / Q000276:immunology; D005260:Female; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D010534:Peritoneal Neoplasms / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D007371:Interferon-gamma