Breast carcinoma cells promote the differentiation of CD34+ progenitors towards 2 different subpopulations of dendritic cells with CD1a(high)CD86(-)Langerin- and CD1a(+)CD86(+)Langerin+ phenotypes.
Primary breast carcinoma are frequently infiltrated by dendritic cells (DC). The mechanisms involved in the localization and status of activation of DC within primary breast carcinoma were investigated. CCL20/MIP3alpha, a chemokine involved in immature DC and their precursors attraction, was detected by immunohistochemistry on cryopreserved tissue sections of primary breast tumors and by ELISA and biological assay in metastatic effusion fluids from breast cancer patients but not from other tumors. In vitro, irradiated breast carcinoma cell lines (BCC) as well as their conditioned media promoted CD34+ cell differentiation into CD1a+ Langerhans cells (LC) precursors as early as day 6, while at day 12, 2 different CCR6+ subpopulations of DC with a Langerhans cell (CD1a(+)Langerin(+)CD86+) and an immature DC (CD1a(high)Langerin-CD86(-)HLA-DR(low)CD40(low)) phenotype were observed. This phenomenon was partly driven by a TGFbeta-dependent mechanism since a pan TGFbeta polyclonal antibody completely blocks BCC-induced LC differentiation and partly reduces immature DC development. These DC failed to maturate in response to sCD40L or LPS stimuli and CD1a(high)Langerin(-)CD86- cells have a reduced T-cell stimulatory capacity in MLR experiments. The absolute number of T cells was reduced by 50% in both the CD4+ or CD8+ compartments, these T cells expressing lower levels of the CD25 Ag and producing less IFNgamma. These results show that breast carcinoma cells produce soluble factors, which may attract DC and their precursors in vivo, and promote the differentiation of the latter into LC and immature DC with altered functional capacities. The infiltration of BCC by these altered DC may contribute to the impaired immune response against the tumor.
Thomachot
Marie Cécile
MC
Equipe Cytokines et Cancers, INSERM U-590, Centre Léon B, Lyon, France.
Bendriss-Vermare
Nathalie
N
Massacrier
Catherine
C
Biota
Cathy
C
Treilleux
Isabelle
I
Goddard
Sophie
S
Caux
Christophe
C
Bachelot
Thomas
T
Blay
Jean Yves
JY
Menetrier-Caux
Christine
C
D015703:Antigens, CD / Q000096:biosynthesis*; D018949:Antigens, CD1 / Q000096:biosynthesis*; D018952:Antigens, CD34 / Q000096:biosynthesis*; D000954:Antigens, Surface / Q000378:metabolism*; D051940:B7-2 Antigen; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000378:metabolism; D002633:Chemotaxis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D037181:Lectins, C-Type / Q000378:metabolism*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009362:Neoplasm Metastasis; D010641:Phenotype; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015703:Antigens, CD; D018949:Antigens, CD1; D018952:Antigens, CD34; D000954:Antigens, Surface; D051940:B7-2 Antigen; C108355:CCL20 protein, human; C419393:CD1a antigen; C121916:CD207 protein, human; C497964:CD86 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D017077:Culture Media, Conditioned; D016207:Cytokines; D037181:Lectins, C-Type; D019402:Macrophage Inflammatory Proteins; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta