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Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity

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Abstract

Despite its potent immunostimulatory properties, vaccination with autologous tumor-derived gp96 has relatively modest antitumor effect in a range of clinical trials. Based on our previous study showing a gp96-mediated immune balance between CTL and Tregs, here we investigated possible synergy between gp96 vaccine and systemic Treg depletion on induction of antitumor T-cell immunity and the mechanisms accounting for synergistic efficacy. In gp96–peptide complex immunized BALB/c mice, anti-CD25 mAb treatment significantly increased IFN-γ-producing CD8+ and CD4+ T cells by about 1–2-fold in spleen and 40–50% in lymph node. A significantly higher number of peptide-specific CTL were observed under anti-CD25 mAb treatment compared with no treatment. Moreover, Treg depletion synergistically improved the anticancer activity of tumor-derived gp96 vaccine in the poorly immunogenic and highly tumorigenic B16 melanoma model in C57BL/6 J mice. While gp96 immunization alone led to the modest enhancement of CTL activities in spleen, the combination with Treg depletion dramatically increased tumor-specific CTL responses. In addition, the combination resulted in a significant increase of CD8+ T-cell infiltration in tumor, which correlated with an enhanced inhibition of tumor growth. Our results provide evidence that targeting Tregs may provide a more efficient strategy to potentiate gp96-mediated T-cell responses and enhance the antitumor efficiency of gp96-based therapeutic vaccine.

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Acknowledgments

The authors thank Fulian Liao for her technical help and advices in cell culture, Chunbao Zhou and Jinhong Yuan for their skillful technical assistance in flow cytometric analysis. This work was supported by a grant from Major State Basic Research Development Program of China (No.2007CB512802), grants from the National Natural Science Foundation of China (NSFC, 30970146, 91029724, 81021003) and the CAS projects (KSCX2-YW-R-1, KSCX2-YW-R-183) and supported by Beijing Natural Science Foundation (Role of heat-shock protein gp96 in antigen presentation and development of new gp96-based vaccines).

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The authors declare no financial or commercial conflict of interest.

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Authors and Affiliations

  1. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), NO.1 West Beichen Road, Chaoyang District, Beijing, 100101, China

    Xiaoli Yan, Xiaojun Zhang, Yanzhong Wang, Xinghui Li, Saifeng Wang, Bao Zhao, Yang Li, Ying Ju, Lizhao Chen, Wenjun Liu & Songdong Meng

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  1. Xiaoli Yan
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  2. Xiaojun Zhang
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  3. Yanzhong Wang
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  4. Xinghui Li
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  7. Yang Li
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  11. Songdong Meng
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Correspondence to Songdong Meng.

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Xiaoli Yan and Xiaojun Zhang contributed equally to this work.

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Yan, X., Zhang, X., Wang, Y. et al. Regulatory T-cell depletion synergizes with gp96-mediated cellular responses and antitumor activity. Cancer Immunol Immunother 60, 1763–1774 (2011). https://doi.org/10.1007/s00262-011-1076-5

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