Enhancement of anti-tumor activity in vitro and in vivo by CD150 and SAP.
Signaling lymphocyte activation molecule (SLAM, CD150) is a co-stimulatory receptor involved in T cell activation. The activity of CD150 is dependent on the intracellular signaling molecule SAP. Here, we investigated anti-CD3 activated human lymphocytes, transfected either with CD150-plasmid or with CD150- or SAP-siRNA in cytotoxicity assays against human colon cancer cells in vitro and in a xenograft model (CB/Scid/CrL mice) in vivo. Up-regulation or silencing of CD150 was accompanied by increased or decreased cytotoxic activity, respectively. Similar effects could also be shown in an IFN-gamma ELISpot assay. Furthermore, CD150 co-localized after activation with lipid rafts in specific membrane compartments on CD8 T cells. Treatment of xenografted mice with CD150 over-expressing lymphocytes decelerated tumor growth significantly. Lymphocytes were detectable in spleen 18 days after injection and expressed mainly CD8, CD45RO and CD150 above average. In conclusion, over-expression of CD150 in lymphocytes is accompanied with enhanced cytotoxic activity and IFN-gamma secretion in vitro and anti-tumor activity in vivo, whereas silencing of CD150 down-regulates effector functions. Adoptive cell transfer of CD150 over-expressing lymphocytes results in an accumulation of CD8, CD45RO and CD150 cells in tumor and spleen indicating together with the observed CD150 co-localization with lipid rafts that CD150 mediates a Th1 response.
Mehrle
Stefan
S
Department of Surgery, University of Heidelberg, 69120 Heidelberg, Germany.
Schmidt
Jan
J
Büchler
Markus W
MW
Watzl
Carsten
C
Märten
Angela
A
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology / Q000473:pathology; D051379:Mice; D011956:Receptors, Cell Surface / Q000276:immunology*; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013154:Spleen / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D015854:Up-Regulation / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; C114953:SH2D1A protein, human; C000604059:SLAMF1 protein, human; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens