Dendritic cells as therapeutic vaccines against cancer

Banchereau, Jacques; Palucka, A. Karolina

doi:10.1038/nri1592

Cited by 1,070 publications

(918 citation statements)

References 139 publications

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“…DCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4].…”

Section: Introductionmentioning

confidence: 99%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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DCs represent the major cell type leading to polarized T-helper (Th) cell responses in vivo. Here, we asked whether the instruction of murine Th2 responses by DCs matured with the proinflammatory cytokine TNF is qualitatively different from maturation by different types of TLR4/MyD88-dependent variant-specific surface glycoproteins (VSGs) of Trypanosoma brucei (T. brucei). The results obtained by analyzing DC surface markers, Notch ligand mRNA, cytokines, asthma, and experimental autoimmune encephalomyelitis (EAE) models as well as performing microarrays indicate that both types of stimuli induce similar inflammatory, semi-mature DC profiles. DCs matured by TNF or VSG treatment expressed a common inflammatory signature of 24 genes correlating with their Th2-polarization capacity. However, the same 24 genes and 4498 additional genes were expressed by DCs treated with LPS that went on to induce Th1 cells. These findings support the concept of a default pathway for Th2-cell induction in DCs matured under suboptimal or inflammatory conditions, independent of the surface receptors and signaling pathways involved. Our data also indicate that quantitative differences in DC maturation might direct Th2-vs Th1-cell responses, since suboptimally matured inflammatory DCs induce default Th2-cell maturation, whereas fully mature DCs induce Th1-cell maturation.Key words: DCs . microarray . Th2 cells . TNF . Trypanosoma Supporting Information available online IntroductionDCs play a fundamental role in the induction of adaptive immune responses as well as in the maintenance of peripheral tolerance [1][2][3]. Through the expression of pattern-recognition receptors (PPRs) such as Toll-like receptors (TLRs), DCs are able to sense a wide array of pathogens and mount an appropriate T-helper (Th) cell response [4]. Naïve CD4 1 T-cell precursors can differentiate into a variety of Th-cell lineages characterized by the cytokines produced: Th1 cells secrete predominately IFN-g, Th2 cells release IL-4, IL-5, and IL-13 and Th17 cells typically produce . Although the contribution of DCs for CD4 1 Th-cell polarization is under debate [6], several DC-derived mechanisms have been described to significantly direct Th-cell phenotypes. 3479DCs change their maturation status by upregulating surface expression of MHC class II and costimulatory molecules and by producing a defined set of cytokines to optimally induce distinct Th-cell responses [7][8][9]. Due to their immunostimulatory function, DCs are of particular interest in immunotherapy settings, such as cancer therapy and infectious disease intervention [10,11]. Thus, the Th-cell polarizing profile defined by the maturation signature of DCs is of vital interest. Several membrane markers on DCs and soluble factors secreted by DCs have been described to polarize toward Th2 responses. These include costimulatory molecules such as OX40 [12], , the Notch family member Jagged-2 [14], the cytokine IL-6 [15], or arachidonic acid metabolites such as PGE 2 [16][17][18]. Much less is known about the fac...

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Section: Introductionmentioning

confidence: 99%

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Pletinckx

Stijlemans²,

Pavlović

et al. 2011

Eur J Immunol

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“…At the level of cellular gene therapy, IL-4-expressing transduced T cells [26,27] or dendritic cells (DCs) [28] have been used with some success. Unlike antigen-specific and/or regulatory T cells, autologous DCs are easy to generate and have been safely used in numerous human clinical trials for therapeutic vaccination against cancer [29] and chronic viral infections [30]. Because of their ability to migrate to selective tissues and lymph nodes to regulate immune responses, DCs represent an attractive cellular candidate to be used in adoptive cellular therapy of autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Creusot

Yaghoubi²,

Kodama

et al. 2008

Clinical Immunology

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A deficit in IL-4 production has been previously reported in both diabetic human patients and nonobese diabetic (NOD) mice. In addition, re-introducing IL-4 into NOD mice systemically, or as a transgene, led to a beneficial outcome in most studies. Here, we show that prediabetic, 12-wk old female NOD mice have a deficit in IL-4 expression in the pancreatic lymph nodes (PLN) compared to age-matched diabetes-resistant NOD.B10 mice. By bioluminescence imaging, we demonstrated that the PLN was preferentially targeted by bone marrow-derived dendritic cells (DCs) following intravenous (IV) administration. Following IV injection of DCs transduced to express IL-4 (DC/ IL-4) into 12-wk old NOD mice, it was possible to significantly delay or prevent the onset of hyperglycemia. We then focused on the PLN to monitor, by microarray analysis, changes in gene expression induced by DC/IL-4 and observed a rapid normalization of the expression of many genes, that were otherwise under-expressed compared to NOD.B10 PLN. The protective effect of DC/IL-4 required both MHC and IL-4 expression by the DCs. Thus, adoptive cellular therapy, using DCs modified to express IL-4, offers an effective, tissue-targeted cellular therapy to prevent diabetes in NOD mice at an advanced stage of pre-diabetes, and may offer a safe approach to consider for treatment of high risk human pre-diabetic patients.

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“…DCs have attracted much interest during the past decades for their use in therapeutic vaccination against cancer, owing to their professional antigen‐specific T cell immunity. Clinical trials have shown that the use of tumour antigen‐loaded DCs in cancer patients is safe; however, their potential in inducing anti‐tumour immunity to eradicate tumours is seen in only a minority of patients 1, 2. This underscores the necessity to redesign and optimize current procedures for DC vaccine manufacture.…”

Section: Introductionmentioning

confidence: 99%

Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors

Eiraku

Yagi

Deng

et al. 2018

Clinical and Experimental Immunology

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SummaryThe finding that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs for developing more effective vaccines for DC therapy. The expression of cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) presents a unique opportunity to target these viral proteins for tumour immunotherapy. Here, we demonstrate that Vγ9γδT cells, innate immune cells activated by zoledronate (Z) and Vα24 natural killer (Vα24NK) cells, innate/adaptive immune cells activated by α‐galactosylceramide (G) can link innate and adaptive immunities through cross‐talk with interferon (IFN) DCs from patients with glioblastoma multiforme (GBM) and healthy donors in a manner that can amplify the activation and proliferation of CMVpp65‐specific CD8+ T cells. The IFN DCs derived from patients with GBM used in this study express lower levels of programmed cell death ligand (PD)‐L1 and PD‐L2 and higher levels of C‐C receptor 7 (CCR7) than the most commonly used mature interleukin (IL)‐4 DCs. The expression level of programmed cell death 1 (PD‐1) on CD8+ T cells, including CMVpp65‐specific CD8+ T cells, expanded by IFN DCs pulsed with the CMVpp65‐peptide and Z plus G (IFN DCs/P+Z+G), was lower than that expanded by IFN DCs pulsed with the peptide alone (IFN DCs/P). Multi‐functional T cells, including human leucocyte antigen (HLA)‐A*0201‐restricted CMVpp65‐specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells, efficiently kill the HLA‐A*0201‐positive GBM cell line expressing CMVpp65 protein (T98G). These findings indicate that DC therapy using IFN DCs/P+Z+G and/or CTL therapy using CMVpp65‐specific CD8+ T cells expanded by IFN DCs/P+Z+G may lead to a good clinical outcome for patients with GBM.

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Dendritic cells as therapeutic vaccines against cancer

Cited by 1,070 publications

References 139 publications

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Similar inflammatory DC maturation signatures induced by TNF or Trypanosoma brucei antigens instruct default Th2‐cell responses

Tissue-targeted therapy of autoimmune diabetes using dendritic cells transduced to express IL-4 in NOD mice

Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors

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