Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo

Biglari, Alireza; Southgate, Thomas D.; Fairbairn, Leslie J.; Gilham, David E.

doi:10.1038/sj.gt.3302706

Cited by 50 publications

(25 citation statements)

References 31 publications

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“…39 Studies using a chimeric receptor consisting of carcinoembryonic antigen-specific scFv fused to the cytosolic tail of Fc␥RI have demonstrated the potent cytotoxic effects mediated through this receptor. 40 Direct targeting of Fc␥RI by expressing scFv-H22 on tumor cell lines showed similar results. 41 Our data provide new insights into the role of Fc␥RI in biology, although the precise mechanism underlying Fc␥RI inside-out regulation needs to be elucidated.…”

Section: Discussionsupporting

confidence: 60%

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Poel

Karssemeijer

Boross

et al. 2010

Blood

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IntroductionFc receptors are receptors for immunoglobulins that play a central role in immunity. On human leukocytes, a myriad of Fc␥ receptors are expressed; among these receptors, Fc␥RI is the only known high-affinity receptor for immunoglobulin G (IgG). 1 Fc␥RI is constitutively expressed on monocytes, macrophages, and myeloid dendritic cells. Interferon␥ (IFN␥) can enhance surface expression of Fc␥RI on these cells, and Fc␥RI expression can be induced on granulocytes by IFN␥ or granulocyte colony-stimulating factor (G-CSF) stimulation. In contrast, cytokines such as interleukin-4 (IL-4), IL-10, and transforming growth factor-␤ (TGF-␤) downregulate activating Fc receptors, including Fc␥RI, and enhance expression of the inhibitory receptor Fc␥RIIb. 2,3 In vitro, IFN␥ treatment leads to increased Fc␥ receptor-induced cytokine production. 4 In vivo, the role of Fc␥RI in immunity remains unclear, as due to its high affinity Fc␥RI is believed to be saturated with monomeric IgG. This has led to the concept that prebound monomeric IgG prevents participation of Fc␥RI in clearing immune complexes by extravasated effector cells. 5 Nevertheless, several in vivo studies documented a role for Fc␥RI, varying from a contribution during inflammation and autoimmune reactions, 6-8 or, during monoclonal antibody (mAb)-based immunotherapy in melanoma and B-cell lymphoma models, 9,10 to a malaria model in which transgenic expression of human Fc␥RI was central for effective mAb treatment. 11 Furthermore, Fc␥RI can induce potent proinflammatory signaling compared with Fc␥RIIa, 12 and can efficiently mediate both major histocompatibility complex class II (MHC-II) antigen presentation and cross-presentation. [13][14][15][16] It remains unclear how Fc␥RI contributes to immune complex clearance in the presence of high IgG levels. For Fc␣RI 17,18 and Fc␥RIIa 19,20 it has been shown that cytokine stimulation can increase ligand binding of these receptors. This appears analogous to inside-out regulation described for integrins. Many integrins are expressed in a low-affinity binding state, which can be transformed to a high-affinity form upon cellular activation. 21 We hypothesized that inside-out regulation could contribute to immune complex binding to Fc␥R occupied by IgG. Indeed, several studies support intracellular proteins interacting with Fc␥RI and possibly affecting ligand binding. 22,23 In this study, we investigated the effect of cytokine stimulation on Fc␥RI ligand binding. Stimulation of Fc␥RI-expressing Ba/F3 cells and primary monocytes resulted in increased binding of immune complexes, whereas binding of monomeric IgG was only moderately enhanced. Upon cellular activation, Fc␥RI could readily bind immune complexes despite pre-engaged monomeric IgG. Taken together, these data might explain how Fc␥RI supports leukocyte interaction with immune complexes. Methods Antibodies and reagentsAnti-Fc␥RI-A647 was from BioLegend (clone 10.1). Unlabeled 10.1 mAb and mouse IgG1/IgG2a isotype were from eBioscience and BD Pharmingen, respect...

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Section: Discussionsupporting

confidence: 60%

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Poel

Karssemeijer

Boross

et al. 2010

Blood

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“…Anticancer effect of human monocyte-derived macrophages genetically modified to express cancer antigen-specific scFv has been reported by Biglari et al 46 In this study, iPS-MP expressing anti-human CD20 scFv inhibited the growth of human B-cell leukemia cells in vitro and in vivo, suggesting a possibility of anticancer therapy with iPS-MP expressing anticancer antigen scFv. The repetitive administration of a large number of macrophages may be necessary to obtain therapeutic effect in clinical settings.…”

Section: Discussionmentioning

confidence: 68%

Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy

et al. 2011

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This report describes generation of dendritic cells (DCs) and macrophages from human induced pluripotent stem (iPS) cells. iPS cell-derived DC (iPS-DC) exhibited the morphology of typical DC and function of T-cell stimulation and antigen presentation. iPS-DC loaded with cytomegalovirus (CMV) peptide induced vigorous expansion of CMV-specific autologous CD8 + T cells. Macrophages (iPS-MP) with activity of zymosan phagocytosis and C5a-induced chemotaxis were also generated from iPS cells. Genetically modified iPS-MPs were generated by the introduction of expression vectors into undifferentiated iPS cells, isolation of transfectant iPS cell clone and subsequent differentiation. By this procedure, we generated iPS-MP expressing a membranebound form of single chain antibody (scFv) specific to amyloid b (Ab), the causal protein of Alzheimer's disease. The scFvtransfectant iPS-MP exhibited efficient Ab-specific phagocytosis activity. iPS-MP expressing CD20-specific scFv engulfed and killed BALL-1 B-cell leukemia cells. Anti-BALL-1 effect of iPS-MP in vivo was demonstrated in a xeno-transplantation model using severe combined immunodeficient mice. In addition, we established a xeno-free culture protocol to generate iPS-DC and iPS-MP. Collectively, we demonstrated the possibility of application of iPS-DC and macrophages to cell therapy.

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“…Some earlier studies were performed in other cell types including monocytes [73], neutrophils, NK cells [74], and dendritic cells [75], but these studies were relatively few. Redirection of cellular function was demonstrated against tumor cells that included cytotoxicity and secretion of inflammatory mediators such as IL-12 and MCP-1.…”

Section: Progress In Cell Productionmentioning

confidence: 99%

Genetic redirection of T cells for cancer therapy

Westwood

Kershaw

2010

Journal of Leukocyte Biology

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Adoptive immunotherapy can induce dramatic tumor regressions in patients with melanoma or viral-induced malignancies, but extending this approach to many common cancers has been hampered by a lack of naturally occurring tumor-specific T cells. In this review, we describe recent advances in the genetic modification of T cells using genes encoding cell-surface receptors specific for tumor-associated antigen. Using genetic modification, the many functional properties of T cells, including cytokine secretion and cytolytic capacity, are redirected from their endogenous specificity toward the elimination of tumor cells. Advances in gene design, vectors, and cell production are discussed, and details of the progress in clinical application of this approach are provided.

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Human monocytes expressing a CEA-specific chimeric CD64 receptor specifically target CEA-expressing tumour cells in vitro and in vivo

Cited by 50 publications

References 31 publications

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG

Generation of dendritic cells and macrophages from human induced pluripotent stem cells aiming at cell therapy

Genetic redirection of T cells for cancer therapy

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