Blood monocytes from mammary tumor-bearing mice: early targets of tumor-induced immune suppression?
We have previously shown that peritoneal macrophages from mice bearing advanced D1-DMBA3 mammary tumors are impaired in their inflammatory functions but are not alternatively activated either and are less differentiated than the ones from normal mice. However, little is known about whether similar defects exist in their precursor stages as blood monocytes. We examined if blood monocytes from mammary tumor-bearing mice are already altered in their activation profiles before becoming macrophages and whether they correspond to inflammatory or resident monocyte subtypes. Much effort is currently devoted to reversing macrophage adverse traits in tumor hosts; as these cells reside within tissues, access is limited. Blood monocytes could be better targeted and manipulated by less invasive means. In the present study, mononuclear cells were isolated from whole blood of D1-DMBA-3 mammary tumor-bearing and normal BALB/c mice and CD115(+) monocytes were analyzed. Our results show that there is an increase in circulating monocytes in tumor hosts; these monocytes exhibit a reduced expression of several myeloid differentiation markers such as CD115, F4/80, CD68 and CD11b. Moreover, downregulation of MHC II, CD62L and the proangiogenic marker Tie-2 are observed in these cells, whereas Gr-1 and Ly6C are upregulated. Furthermore, gene microarray analysis performed for the first time in blood monocytes from tumor hosts indicates that they express a mixture of pro-inflammatory and anti-inflammatory cytokines and chemokines. Interestingly, CCR2 and CX3CR1, which are crucial in monocyte definition as inflammatory or resident, respectively, are both upregulated. Importantly, complement proteins are enhanced whereas nitric oxide production is decreased and there is no measurable arginase activity detected in these cells. Collectively, our study represents the first comprehensive analysis of blood monocytes from tumor-bearing mice; we conclude that these cells are neither completely inflammatory nor suppressive and are less differentiated, similar to the macrophages they later become.
Caso
Raul
R
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, FL 33101, USA.
Silvera
Risset
R
Carrio
Roberto
R
Iragavarapu-Charyulu
Viyaya
V
Gonzalez-Perez
Ruben R
RR
Torroella-Kouri
Marta
M
D000230:Adenocarcinoma / Q000097:blood / Q000235:genetics / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000950:Antigens, Ly / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002469:Cell Separation; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D007958:Leukocyte Count; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology*; D009569:Nitric Oxide / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D042787:Receptor, TIE-2; D019139:Tumor Escape / Q000235:genetics; D000097382:CD68 Molecule
D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D000950:Antigens, Ly; D001119:Arginase; D039481:CD11b Antigen; D018925:Chemokines; D003165:Complement System Proteins; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D019041:L-Selectin; D009569:Nitric Oxide; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D042787:Receptor, TIE-2; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C494192:Ly-6C antigen, mouse; C036763:monocyte-macrophage differentiation antigen; C079086:Tek protein, mouse