Gene therapy to target dendritic cells from blood to lymph nodes

Robert, Caroline; Klein, Christoph; Cheng, George; Kogan, Avi N; Mulligan, Richard C.; Andrian, Ulrich H. von; Kupper, Thomas S.

doi:10.1038/sj.gt.3302008

Cited by 25 publications

(15 citation statements)

References 28 publications

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“…Although the possible re-emergence of mature DC into the blood has been documented (46), such mature DC would be unable to migrate back to peripheral tissues. Furthermore, because these cells lack the expression of L-selectin (CD62L) (47) (data not shown), they cannot enter lymph nodes via blood circulation (48,49). This finding is of particular importance in the context of immunotherapy using monocyte-derived DC, because i.v.…”

Section: Discussionmentioning

confidence: 94%

Sialyl-Lewisx on P-Selectin Glycoprotein Ligand-1 Is Regulated during Differentiation and Maturation of Dendritic Cells: A Mechanism Involving the Glycosyltransferases C2GnT1 and ST3Gal I

Julien

Grimshaw

Sutton-Smith

et al. 2007

The Journal of Immunology

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To fulfil their function as APCs, dendritic cells (DC) and their precursors need to travel from blood to the peripheral tissues and, upon activation, migrate from tissues to draining lymph nodes. Because O-glycans play a role in T cell trafficking, we investigated the O-glycosylation profile of human monocyte-derived DC. Sialyl-Lewisx (sLex), a glycan involved in extravasation via selectin binding, was found to be expressed exclusively on P-selectin glycoprotein ligand-1 in monocytes and immature DC. However, sLex was lost from mature DC even though these cells retained expression of P-selectin glycoprotein ligand-1. Maturation of DC led to a rapid change in the expression of glycosyltransferases involved in O-linked glycosylation. A down-regulation of C2GnT1 mRNA and enzymatic activity was observed with a concurrent up-regulation of ST3Gal I and ST6GalNAc II mRNA resulting in a loss of the core 2 structures required for sLex expression as a P-selectin ligand. Interestingly, the early regulation of these glycosyltransferases was mediated by PGE2, which is known to be required for human DC migration. The pattern of O-glycosylation seen in mature cells was very similar to that expressed by naive T cells, which home to lymph nodes. Our data show that the regulation of O-glycosylation controls sLex expression, and also suggest that O-glycans may have a function in DC migration.

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Section: Discussionmentioning

confidence: 94%

Sialyl-Lewisx on P-Selectin Glycoprotein Ligand-1 Is Regulated during Differentiation and Maturation of Dendritic Cells: A Mechanism Involving the Glycosyltransferases C2GnT1 and ST3Gal I

Julien

Grimshaw

Sutton-Smith

et al. 2007

The Journal of Immunology

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“…To this end, DCs can be gene-modified to express chemokines, such as lymphotactin (Cao et al, 1998) and secondary lymphoid tissue chemokine (SLC or CCL-21) (Kirk et al, 2001a,b;Matsuyoshi et al, 2004;Yang et al, 2004), in order to attract T cells to facilitate their activation. Another strategy to bring DCs into contact with T cells is through gene transfer of homing molecules, such as E=L-selectin, in order for them to migrate to the T cell zones of peripheral lymph nodes where activation could take place (Robert et al, 2003;Dorrie et al, 2008).…”

Section: Cytokines and Chemokines: Signalmentioning

confidence: 99%

Dendritic Cell-Based Cancer Gene Therapy

Smits

Anguille²,

Cools³

et al. 2009

Human Gene Therapy

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In view of their potent antigen-presenting capacity and ability to induce effective immune responses, dendritic cells (DCs) have become an attractive target for therapeutic manipulation of the immune system. The application of tumor-associated antigen (TAA)-expressing DCs for cancer therapy has been the subject of intensive translational investigation. Previous clinical trials demonstrated tumor-specific immune responses without any significant toxicity. However, the clinical success has been modest, because only a limited number of immunized patients demonstrated cancer regression. Considerable progress has been made in the knowledge of DC biology, which opens new avenues for the development of optimized clinical protocols. One such promising approach that might carve its place in the future of DC-based therapy is the use of gene-modified DCs. DCs engineered to express TAAs allow multiepitope presentation by both major histocompatibility complex (MHC) class I and II molecules of full-length TAAs independent of the patient's HLA constitution, as opposed to peptide vaccination strategies. Besides transgene TAA expression, DCs can be genetically modified (1) to express a variety of immune-potentiating molecules (e.g., costimulatory molecules, cytokines, and chemokines) or (2) to downregulate negative modulators of DC functioning, all allowing an enhancement of their immunogenic potential. In the present review, gene delivery systems for DCs are discussed, as well as the various transgenes used for genetic modification of DCs. Moreover, a detailed review of the already published trials using gene-modified DCs is presented and future DC-based strategies targeting multiple layers of the complex cellular immune response are highlighted.

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“…To confirm a requirement for L-selectin in leukemic engraftment, we used a retroviral vector to coexpress a chimeric E/L-selectin fusion protein, consisting of the extracellular domain of E-selectin fused to the transmembrane and intracellular domains of L-selectin, 51,52 together with BCR-ABL1. Coexpression of E/L-selectin rescued the leukemogenic defect of L-selectin-deficient BM, with 100% of recipient mice developing CML-like leukemia with the same latency as recipients of WT BM ( Figure 6A-B), whereas coexpression of E/Lselectin with BCR-ABL1 in WT BM did not significantly alter the CML-like disease (data not shown).…”

Section: 49mentioning

confidence: 99%

Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche

Krause

Lazarides

Lewis

et al. 2014

Blood

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Key Points• In a mouse model, BCR-ABL1 1 leukemia stem cells are more dependent on selectins and their ligands for homing and engraftment than normal HSCs.• Blockade of selectin-ligand interactions might prevent leukemic engraftment and relapse in autografted patients.We investigated adhesion pathways that contribute to engraftment of breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1)-induced chronic myelogenous leukemia (CML)-like myeloproliferative neoplasia in a mouse retroviral transduction/transplantation model. Compared with normal stem/progenitor cells, BCR-ABL1 1 progenitors had similar expression of very late antigen-4 (VLA4), VLA5, leukocyte functional antigen-1, and CXCR4 but lower expression of P-selectin glycoprotein ligand-1 (PSGL-1) and of L-selectin. Whereas vascular cell adhesion molecule-1 and P-selectin were not required, deficiency of E-selectin in the recipient bone marrow endothelium significantly reduced engraftment by BCR-ABL1-expressing stem cells following intravenous injection, with leukemogenesis restored by direct intrafemoral injection. BCR-ABL1-expressing cells deficient for PSGL-1 or the selectin ligand-synthesizing enzymes core-2 b1,6-N-acetylglucosaminyltransferase or fucosyltransferases IV/VII were impaired for engraftment, and destruction of selectin ligands on leukemic progenitors by neuraminidase reduced engraftment. BCR-ABL1-expressing L-selectin-deficient progenitors were also defective in homing and engraftment, with leukemogenesis rescued by coexpression of chimeric E/L-selectin. Antibody to L-selectin decreased the engraftment of BCR-ABL1-transduced stem cells. These results establish that BCR-ABL11 leukemic stem cells rely to a greater extent on selectins and their ligands for homing and engraftment than do normal stem cells. Selectin blockade is a novel strategy to exploit differences between normal and leukemic stem cells that may be beneficial in autologous transplantation for CML and perhaps other leukemias. (Blood. 2014;123(9):1361-1371

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Gene therapy to target dendritic cells from blood to lymph nodes

Cited by 25 publications

References 28 publications

Sialyl-Lewisx on P-Selectin Glycoprotein Ligand-1 Is Regulated during Differentiation and Maturation of Dendritic Cells: A Mechanism Involving the Glycosyltransferases C2GnT1 and ST3Gal I

Sialyl-Lewisx on P-Selectin Glycoprotein Ligand-1 Is Regulated during Differentiation and Maturation of Dendritic Cells: A Mechanism Involving the Glycosyltransferases C2GnT1 and ST3Gal I

Dendritic Cell-Based Cancer Gene Therapy

Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche

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