Liver sequestration of murine lymphokine activated killer (LAK) cells is mediated by carbohydrate-specific receptors.
Intravenous infusion of radiolabeled lymphokine activated killer (LAK) cells into tumor bearing humans and animals results in retention of a large percentage (40-70%) of cells within the liver. Since LAK cell-tumor cell adhesion is believed to be necessary to initiate effective cytotoxicity, liver sequestration may decrease the therapeutic effectiveness of the adoptively transferred cells. We evaluated the mechanism of liver sequestration in a murine model. When 51Cr labeled LAK cells were infused intravenously into syngeneic recipients, about 45% of the radiolabeled cells were sequestered in the liver by 4 hours after infusion and 55% by 24 hours. Less than 0.4% of the infused cells localized into a 3-4 mm tumor implant. Peanut agglutinin (PNA), which recognizes galactose-terminal glycans, identifies cells at risk for sequestration by hepatic asialoglycoprotein receptors. We demonstrated that LAK cells, particularly the large granular lymphocyte subpopulations, were PNA high by direct immunofluorescence. The majority of LAK cell cytotoxic activity also resided in the PNA high cell population. Lectin blotting revealed that IL-2 incubation caused an increased expression of multiple cell membrane asialoglycoproteins. Experiments in vitro suggested that LAK cells were capable of binding to asialoglycoprotein and fucose-specific receptors within the liver. This binding could be inhibited by mild LAK cell surface trypsinization, suggesting that binding was mediated via cell surface glycoproteins. We conclude that LAK cells have a surface phenotype which can mediate their interaction with multiple hepatic carbohydrate-specific receptors. These interactions may result in LAK cell sequestration and decrease the delivery of cytotoxic cells into cancers during adoptive immunotherapy.
Samlowski
W E
WE
Salt Lake City Veterans Administration Medical Center, UT.
McGregor
J R
JR
Litton
G J
GJ
D000818:Animals; D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D002240:Carbohydrate Sequence; D002465:Cell Movement / Q000502:physiology; D002860:Chromium Radioisotopes; D060748:Fetuins; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000502:physiology; D015979:Killer Cells, Lymphokine-Activated / Q000502:physiology*; D037102:Lectins; D008099:Liver / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D019887:Peanut Agglutinin; D010447:Peptide Hydrolases; D010641:Phenotype; D011971:Receptors, Immunologic / Q000378:metabolism*; D000509:alpha-Fetoproteins / Q000378:metabolism
D037263:Asialoglycoprotein Receptor; D001212:Asialoglycoproteins; D002860:Chromium Radioisotopes; D060748:Fetuins; D007376:Interleukin-2; D037102:Lectins; D019887:Peanut Agglutinin; D011971:Receptors, Immunologic; D000509:alpha-Fetoproteins; C017029:asialofetuin; D010447:Peptide Hydrolases