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Induction of protective cytotoxic T-cell responses by a B-cell-based cellular vaccine requires stable expression of antigen

Gene Therapy volume 16, pages 1300–1313 (2009)Cite this article

Abstract

B-cell-based cellular vaccines represent a promising approach to active immunotherapy of cancer complementing the use of dendritic cells, especially in pediatric patients and patients with low bone marrow reserves. B cells can be easily prepared in large numbers and readily home to secondary lymphoid organs, the primary site of induction of cytotoxic T lymphocyte (CTL) responses. However, most B-cell-based vaccines tested so far failed to induce functional and protective CTLs in in vivo models. Here, we show that B-cells activated through the toll-like receptor-9 (TLR-9) and CD40 up-regulate surface expression of major histocompatibility complex and costimulatory molecules, produce IL-12, and exhibit potent antigen-presenting properties in vitro. Importantly, although administration of peptide-coated or transiently transfected B cells fails to induce immune responses, therapeutic immunization with low numbers of genetically modified B cells stably expressing antigen results in an induction of functional CTLs and protection against the growth of tumor in an animal model. After activation, B cells partially loose their ability to home to organized lymphoid tissue because of the shedding of CD62L; however, this property can be restored by expression of protease-resistant mutant of CD62L. In summary, the data presented in this report suggest that genetically modified activated B cells represent a promising candidate for a cancer vaccine eliciting functional systemic CTLs.

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Abbreviations

CTL:

cytotoxic T lymphocyte

TLR:

toll-like receptor

CpG/CD40-B cells:

B cells activated by CpG and anti-CD40 antibody

TAA:

tumor-associated antigen

LPS:

bacterial lipopolysaccharide

CFSE:

5-(6)-carboxyfluorescein diacetate succinimidyl ester

ICS:

intracellular cytokine staining

PLN and MLN:

peripheral and mesenteric lymph nodes

PP:

Peyer's patches

CD62L-SR:

sheddase-resistant mutant of CD62L

ICAM-1:

intercellular adhesion molecule-1

HEV:

high endothelial venule.

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Acknowledgements

This work was supported by National Institutes of Health grant AI063967 and by internal funds from Department of Pathology at UAB.

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Authors and Affiliations

  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    S Guo, J Xu & Z Hel

  2. Department of Microbiology,

    W Denning & Z Hel

  3. University of Alabama at Birmingham, Birmingham, AL, USA

    W Denning & Z Hel

  4. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Z Hel

  5. Center for AIDS Research, University of Alabama at Birmingham, Birmingham, AL, USA

    Z Hel

  6. Mucosal HIV and Immunobiology Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Z Hel

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Correspondence to Z Hel.

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Guo, S., Xu, J., Denning, W. et al. Induction of protective cytotoxic T-cell responses by a B-cell-based cellular vaccine requires stable expression of antigen. Gene Ther 16, 1300–1313 (2009). https://doi.org/10.1038/gt.2009.93

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