Subject(s)
B7-H1 Antigen/metabolism , Bone Marrow/metabolism , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/pathology , Neoplasm, Residual/pathology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Tumor Microenvironment , Animals , Case-Control Studies , Cells, Cultured , Female , Follow-Up Studies , Humans , Immunophenotyping , Killer Cells, Natural/metabolism , Killer Cells, Natural/pathology , Mice , Mice, Inbred C57BL , Multiple Myeloma/metabolism , Multiple Myeloma/mortality , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/mortality , Neoplasm Staging , Neoplasm, Residual/metabolism , Neoplasm, Residual/mortality , Prognosis , Programmed Cell Death 1 Receptor/metabolism , Prospective Studies , Stem Cells/metabolism , Stem Cells/pathology , Survival Rate , T-Lymphocytes/metabolism , T-Lymphocytes/pathologyABSTRACT
The surface phenotype CD3-NK1.1+DX5+CD11c(int)B220+GR1- has been recently ascribed to a novel subset of mouse leukocytes termed interferon (IFN)-producing killer dendritic cells (IKDCs) that shares functions with natural killer (NK) cells and DCs. Interleukin-15 (IL-15) is critical for NK cells but its relationship with IKDC remained unexplored. An expression cassette encoding human IL-15 (hIL-15) has been transferred by hydrodynamic injection into the liver of mice, resulting in transient expression of the cytokine that is detectable during the first 48 h. hIL-15 hydrodynamic gene transfer resulted in an expansion of NK cells and IKDCs. Relative expansions of IKDCs were more dramatic in the IL-15 gene-transferred hepatic tissue than in the spleen. Adoptively transferred DX5+ cells comprising both NK cells and IKDCs proliferated in response to hydrodynamic injection of hIL-15, indicating that quantitative increases are at least in part the result of proliferation from already differentiated cells. Expansion is accompanied by enhanced cytolytic activity and increased expression of TRAIL and CD137 (4-1BB), without augmenting interferon-gamma production. The effects of a single hydrodynamic injection surpassed those of two intraperitoneal doses of the recombinant protein. The novel functional link between circulating IL-15 and IKDCs opens new possibilities to study the biology and applications of this minority cell subset.
Subject(s)
Genetic Therapy/methods , Interleukin-15/genetics , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Liver/immunology , Adoptive Transfer , Animals , Cytotoxicity, Immunologic , Dendritic Cells/immunology , Flow Cytometry , Genes, RAG-1 , Humans , Injections, Intravenous , Interleukin-15/metabolism , Lymphocyte Count , Mice , Mice, Inbred C57BL , Mice, Knockout , Recombinant Proteins , Reverse Transcriptase Polymerase Chain Reaction , Spleen/immunology , Transfection/methodsABSTRACT
Las células mieloides supresoras (Myeloid-derived suppressorcells, MDSC) pertenecen a un subtipo de leucocitos causantes deinmunosupresión en individuos portadores de tumor. En ratones,estas células han sido definidas como CD11b+GR1+IL-4Rá+y, debido a la presencia de tumores en modelos experimentales,se acumulan tanto en la lesión tumoral como en los órganos linfoides.CD137 (4-1BB) es un receptor de coestímulo de la familia dereceptores del factor de necrosis tumoral (TNF) principalmenteexpresado sobre la membrana de linfocitos T y de células NK(Natural Killer) activados, aunque también se encuentra en la superficiede otros leucocitos de estirpe mieloide como mastocitos, granulocitos,macrófagos, células dendríticas y endotelio. Anticuerposagonistas frente a CD137 incrementan la respuesta inmuneantitumoral potenciando los CTLs antitumorales. En este trabajo,células de carcinoma de colon C26 transfectadas para expresarGM-CSF se inocularon por vía subcutánea a ratones singénicosdebido a sus propiedades inductoras de un gran aumento enel número de las MDSCs. Mediante citometría de flujo multicolorhemos confirmado un notable aumento en el número de estascélulas CD11b+GR1+IL-4Rá+ tanto en el estroma tumoral comoen el bazo de los ratones portadores de tumor. La expresión deCD137 en este subtipo celular sin embargo, mostró resultadosnegativos. Por tanto, se pueden excluir los efectos directos de losmAbs sobre MDSCs como mecanismo de acción de la inmunoterapiacon anticuerpos anti-CD137. Según esto las terapias dirigidasa disminuir el número o función de MDSCs podrían sinergizarcon anticuerpos inmunoterapéuticos anti-CD137 ya queactúan sobre dianas diferentes
Myeloid-derived suppressor cells (MDSC) are a subset ofleukocytes associated with local and systemic T-cell immunosuppressionin tumor-bearing hosts. In mice these cells are bestdefined as CD11b+GR1+IL-4Rá+ and their numbers increase inresponse to the presence of an experimental malignancy both atthe tumor lesion and in lymphoid organs. CD137 is a co-stimulatoryreceptor that belongs to the tumor necrosis factor (TNF)receptor family characteristically expressed on activated T cellsand NK cells. Its expression has also been reported on myeloidcells such as mastocytes, granulocytes, macrophages, dendriticcells, and on endothelium. Agonist antibodies against CD137 areknown to increase the antitumor immune response through augmentingthe intensity of antitumor CTLs. In this study C26 coloncarcinoma cells transfected to express GM-CSF were subcutaneouslyimplanted in syngeneic mice because of its properties asthe most potent inducer of MDSCs. Indeed, multicolor flow cytometryconfirmed a dramatic numeric increase in CD11b+GR1+IL-4Rá+ cells both in the tumor stroma and in the spleen of tumorbearingmice. Analysis of CD137 expression on this cell subsetrendered completely negative results. Therefore direct effects ofimmunotherapeutic anti-CD137 monoclonal antibodies on MDSCscan be excluded as a mechanism of action, thus indicating thattherapies aimed at decreasing MDSCs might synergize withimmunotherapeutic anti-CD137 antibody as a result of dealing with different targets
