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Generation of a Novel Dendritic-cell Vaccine Using Melanoma and Squamous Cancer Stem Cells
Published on: January 6, 2014
Genetic vaccines to potentiate the effective CD103+ dendritic cell-mediated cross-priming of antitumor immunity
Yi Zhang1, Guo Chen1, Zuqiang Liu1
1Department of Dermatology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
Abstract:
The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. This deficiency is in part due to an incomplete understanding of how to best invoke dendritic cells (DC) that are crucial for the induction of tumor-specific CD8(+) T cells capable of mediating durable protective immunity. In this regard, elevated expression of the transcription factor X box-binding protein 1 (XBP1) in DC appears to play a decisive role in promoting the ability of DC to cross-present Ags to CD8(+) T cells in the therapeutic setting. Delivery of DNA vaccines encoding XBP1 and tumor Ag to skin DC resulted in increased IFN-α production by plasmacytoid DC (pDC) from skin/tumor draining lymph nodes and the cross-priming of Ag-specific CD8(+) T cell responses associated with therapeutic benefit. Antitumor protection was dependent on cross-presenting Batf3(+) DC, pDC, and CD8(+) T cells. CD103(+) DC from the skin/tumor draining lymph nodes of the immunized mice appeared responsible for activation of Ag-specific naive CD8(+) T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3(+) DC-pDC interactions, thereby enabling effective vaccine induction of protective antitumor immunity.
Insights
Enhancing cancer vaccines requires understanding dendritic cell (DC) function. The transcription factor X box-binding protein 1 (XBP1) in DCs boosts CD8(+) T cell responses, crucial for effective antitumor immunity.
Area of Science:
- Immunology
- Vaccinology
- Cancer Research
Background:
- Effective cancer vaccines are a critical unmet need.
- Dendritic cells (DCs) are crucial for inducing tumor-specific CD8(+) T cell responses.
- The role of transcription factor X box-binding protein 1 (XBP1) in DCs for vaccine efficacy is under investigation.
Purpose of the Study:
- To investigate the role of X box-binding protein 1 (XBP1) in dendritic cells (DCs) for effective cancer vaccine development.
- To determine if XBP1 enhances the cross-presentation of antigens to CD8(+) T cells.
- To elucidate the interaction between different DC subsets in response to XBP1-mediated vaccine strategies.
Main Methods:
- DNA vaccines encoding XBP1 and tumor antigens were delivered to skin DCs in a mouse model.
- Interferon-alpha (IFN-α) production by plasmacytoid DCs (pDCs) and CD8(+) T cell priming were analyzed.
- The function of specific DC subsets (Batf3(+), CD103(+), pDCs) and CD8(+) T cells was assessed.
- The effect of human XBP1 on human DCs and T cell activation was evaluated.
Main Results:
- Delivery of DNA vaccines with XBP1 to skin DCs increased IFN-α production and CD8(+) T cell cross-priming.
- Antitumor protection was dependent on Batf3(+) DCs, pDCs, and CD8(+) T cells.
- CD103(+) DCs activated naive CD8(+) T cells, with pDCs enhancing this process.
- Human XBP1 improved the ability of human DCs to activate human T cells.
Conclusions:
- X box-binding protein 1 (XBP1) plays a crucial intrinsic role in dendritic cells (DCs) for effective cross-priming.
- XBP1 orchestrates interactions between Batf3(+) DCs and pDCs, leading to enhanced vaccine-induced antitumor immunity.
- These findings support XBP1 as a target for improving cancer vaccine efficacy.
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