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Enhancement of antitumor immunity by prolonging antigen presentation on dendritic cells

Nature Biotechnology volume 20, pages 149–154 (2002)Cite this article

Abstract

Vaccination with dendritic cells (DCs) pulsed with antigenic peptides derived from various tumor antigens has great, but as yet significantly unrealized, potential in cancer treatment. Here, we describe a strategy for prolonged presentation of an MHC class I–restricted self-peptide on DCs through linkage of it to a cell penetrating peptide (CPP). DCs loaded with a peptide derived from tyrosinase-related protein 2 (TRP2) covalently linked to a CPP1 sequence retained full capacity to stimulate T cells for at least 24 h, completely protected immunized mice from subsequent tumor challenge, and significantly inhibited lung metastases in a 3-day tumor model. DCs pulsed with TRP2 alone failed to provide any of these protections. In addition, we demonstrate that both CD4+ and CD8+ T cells were required for potent antitumor immunity. This CPP-based approach may be generally applicable to enhance the efficacy of DC-based peptide vaccines against cancer and other diseases.

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Figure 1: Intracellular delivery of CPP1-peptides into dendritic cells and prolonging of their ability to stimulate T cells.
Figure 2: Immunization of mice with mature DCs pulsed with CPP1-TRP2 generates protective immunity.
Figure 3: Comparative analysis of lung metastases and animal survival.
Figure 4: Induction of CD8+ T cell responses after vaccination.
Figure 5: Requirement of CD4+ and CD8+ T cells for antitumor immunity.
Figure 6: Treatment of active B16 tumor with DCs pulsed with the CPP1-TRP2 peptide.

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Acknowledgements

We thank Malcolm Brenner for his helpful suggestions and critical reading of the manuscript and Tihui Fu for assistance in some experiments.

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Authors and Affiliations

  1. The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030, TX

    Rong-Fu Wang & Helen Y. Wang

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  1. Rong-Fu Wang
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Correspondence to Rong-Fu Wang.

Supplementary information

Web Figure 1.

Phenotype characterization and MLR assay of DCs. A) Surface phenotype of mature and immature DCs generated different culture conditions. DCs were stained anti-CD11c-PE along with anti-I-A-FITC, anti-B7-1-FITC and anti-B7-2-FITC, respectively, and analyzed by flow cytometry. Double positive staining of mutaure DC for CD11c and co-stimulatory B7.1, B7.2 and MHC class II molecules was 55-70% while double positive staining for immature DC was only about 15-20%. B) Allogeneic MLR of mature, immature DCs and splenocytes. DCs were cocultured with allogeneic BALB/c T cells isolated from bulk splenocytes by passing cell through an immunoaffinity column. [3H]-thymidine incorporation from triplicate wells were obtained after subtraction of the background counts from irradiated stimulators and T cells alone, and are plotted as the average counts for each stimulator:effector ratio. (GIF 100 kb)

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Wang, RF., Wang, H. Enhancement of antitumor immunity by prolonging antigen presentation on dendritic cells. Nat Biotechnol 20, 149–154 (2002). https://doi.org/10.1038/nbt0202-149

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