Induction of CD4+ T cell–dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells
Helen Y. Wang, Tihui Fu, Gang Wang, Gang Zeng, Donna M. Perry-Lalley, James C. Yang, Nicholas P. Restifo, Patrick Hwu, Rong-Fu Wang
Helen Y. Wang, Tihui Fu, Gang Wang, Gang Zeng, Donna M. Perry-Lalley, James C. Yang, Nicholas P. Restifo, Patrick Hwu, Rong-Fu Wang
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Article Immunology

Induction of CD4+ T cell–dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells

Abstract

Dendritic cell–based (DC-based) immunotherapy represents a promising approach to the prevention and treatment of many diseases, including cancer, but current strategies have met with only limited success in clinical and preclinical studies. Previous studies have demonstrated that a TAT peptide derived from the HIV TAT protein has the ability to transduce peptides or proteins into various cells. Here, we describe the use of TAT-mediated delivery of T cell peptides into DCs to prolong antigen presentation and enhance T cell responses. While immunization of mice with DCs pulsed with an antigenic peptide derived from the human TRP2 protein generated partial protective immunity against B16 tumor, immunization with DCs loaded with a TAT-TRP2 peptide resulted in complete protective immunity, as well as significant inhibition of lung metastases in a 3-day tumor model. Although both DC/TRP2 and DC/TAT-TRP2 immunization increased the number of TRP2-specific CD8+ T cells detected by Kb/TRP2 tetramers, T cell activity elicited by DC/TAT-TRP2 was three- to tenfold higher than that induced by DC/TRP2. Furthermore, both CD4+ and CD8+ T cells were required for antitumor immunity demonstrated by experiments with antibody depletion of subsets of T cells, as well as with various knockout mice. These results suggest that a TAT-mediated antigen delivery system may have important clinical applications for cancer therapy.

Authors

Helen Y. Wang, Tihui Fu, Gang Wang, Gang Zeng, Donna M. Perry-Lalley, James C. Yang, Nicholas P. Restifo, Patrick Hwu, Rong-Fu Wang

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CD4+ and CD8+ T cells are required for antitumor immunity. (a) B6 mice w...
CD4+ and CD8+ T cells are required for antitumor immunity. (a) B6 mice were immunized with DC/TAT-TRP2. Mice were treated with anti-CD4, anti-CD8, and control antibodies on the day before tumor challenge, followed by three injections on days 1, 3, and 10 after tumor injection. Mice immunized with PBS, DC/PBS, and DC/TAT–β-gal were used as control groups for tumor injection and specificity. Lung metastases were counted in each group (n = 5). Similar results were obtained in three repeated experiments. (b) B6, CD4 KO, and CD8 KO mice were immunized with DC/TAT-TRP2, and then challenged with B16 tumor cells. DC/PBS was used as a control (n = 5 per group). The number of lung metastases was counted after 14 days of tumor challenge and plotted as mean numbers of lung metastases. (c) DCs were prepared from class I KO, class II KO, and B6 mice, pulsed with the TAT-TRP2 peptide, and used for immunization of B6 mice. DC/PBS was used as a negative control group. Nonimmunized KO mice failed to produce protective immunity against tumor challenge. The experimental procedure for tumor challenge was the same as shown above.