Original Article

Synergism of Cytotoxic T Lymphocyte–associated Antigen 4 Blockade and Depletion of CD25⁺ Regulatory T Cells in Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive Cytotoxic T Lymphocyte Responses

Correspondence to: Cornelis J.M. Melief, Immunohematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Tel:31-71-526-3800 Fax:31-71-5216751 E-mail:cmelief{at}LUMC.nl.

Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the CD25⁺ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25⁺ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2^180–188–specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8⁺ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25⁺ Treg cells indicates that CD25⁺ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.

Key Words: immunotherapy, melanoma, tolerance, TRP-2, depigmentation

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• Ko, K., Yamazaki, S., Nakamura, K., Nishioka, T., Hirota, K., Yamaguchi, T., Shimizu, J., Nomura, T., Chiba, T., Sakaguchi, S. (2005). Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. JEM 202: 885-891 [Abstract] [Full Text]  
• Wei, W.-Z., Jacob, J. B., Zielinski, J. F., Flynn, J. C., Shim, K. D., Alsharabi, G., Giraldo, A. A., Kong, Y.-c. M. (2005). Concurrent Induction of Antitumor Immunity and Autoimmune Thyroiditis in CD4+CD25+ Regulatory T Cell-Depleted Mice. Cancer Res. 65: 8471-8478 [Abstract] [Full Text]  
• Beyer, M., Kochanek, M., Darabi, K., Popov, A., Jensen, M., Endl, E., Knolle, P. A., Thomas, R. K., von Bergwelt-Baildon, M., Debey, S., Hallek, M., Schultze, J. L. (2005). Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 106: 2018-2025 [Abstract] [Full Text]  
• Tacken, P. J., de Vries, I. J. M., Gijzen, K., Joosten, B., Wu, D., Rother, R. P., Faas, S. J., Punt, C. J. A., Torensma, R., Adema, G. J., Figdor, C. G. (2005). Effective induction of naive and recall T-cell responses by targeting antigen to human dendritic cells via a humanized anti-DC-SIGN antibody. Blood 106: 1278-1285 [Abstract] [Full Text]  
• den Boer, A. Th., van Mierlo, G. J.D., Fransen, M. F., Melief, C. J.M., Offringa, R., Toes, R. E.M. (2005). CD4+ T Cells Are Able to Promote Tumor Growth through Inhibition of Tumor-Specific CD8+ T-Cell Responses in Tumor-Bearing Hosts. Cancer Res. 65: 6984-6989 [Abstract] [Full Text]  
• Sharma, S., Yang, S.-C., Zhu, L., Reckamp, K., Gardner, B., Baratelli, F., Huang, M., Batra, R. K., Dubinett, S. M. (2005). Tumor Cyclooxygenase-2/Prostaglandin E2-Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer. Cancer Res. 65: 5211-5220 [Abstract] [Full Text]  
• Pace, L., Pioli, C., Doria, G. (2005). IL-4 Modulation of CD4+CD25+ T Regulatory Cell-Mediated Suppression. J. Immunol. 174: 7645-7653 [Abstract] [Full Text]  
• Kudo-Saito, C., Schlom, J., Camphausen, K., Coleman, C. N., Hodge, J. W. (2005). The Requirement of Multimodal Therapy (Vaccine, Local Tumor Radiation, and Reduction of Suppressor Cells) to Eliminate Established Tumors. Clin. Cancer Res. 11: 4533-4544 [Abstract] [Full Text]  
• Chung, Y., Lee, S.-H., Kim, D.-H., Kang, C.-Y. (2005). Complementary role of CD4+CD25+ regulatory T cells and TGF-{beta} in oral tolerance. J. Leukoc. Biol. 77: 906-913 [Abstract] [Full Text]  
• Hodge, J. W., Chakraborty, M., Kudo-Saito, C., Garnett, C. T., Schlom, J. (2005). Multiple Costimulatory Modalities Enhance CTL Avidity. J. Immunol. 174: 5994-6004 [Abstract] [Full Text]  
• Lee, B. P.-L., Mansfield, E., Hsieh, S.-C., Hernandez-Boussard, T., Chen, W., Thomson, C. W., Ford, M. S., Bosinger, S. E., Der, S., Zhang, Z.-x., Zhang, M., Kelvin, D. J., Sarwal, M. M., Zhang, L. (2005). Expression Profiling of Murine Double-Negative Regulatory T Cells Suggest Mechanisms for Prolonged Cardiac Allograft Survival. J. Immunol. 174: 4535-4544 [Abstract] [Full Text]  
• Wan, Y. Y., Flavell, R. A. (2005). Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl. Acad. Sci. USA 102: 5126-5131 [Abstract] [Full Text]  
• Mangeney, M., Pothlichet, J., Renard, M., Ducos, B., Heidmann, T. (2005). Endogenous Retrovirus Expression Is Required for Murine Melanoma Tumor Growth In vivo. Cancer Res. 65: 2588-2591 [Abstract] [Full Text]  
• Tien, A. H., Xu, L., Helgason, C. D. (2005). Altered Immunity Accompanies Disease Progression in a Mouse Model of Prostate Dysplasia. Cancer Res. 65: 2947-2955 [Abstract] [Full Text]  
• Lutsiak, M. E. C., Semnani, R. T., De Pascalis, R., Kashmiri, S. V. S., Schlom, J., Sabzevari, H. (2005). Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105: 2862-2868 [Abstract] [Full Text]  
• Haeryfar, S. M. M., DiPaolo, R. J., Tscharke, D. C., Bennink, J. R., Yewdell, J. W. (2005). Regulatory T Cells Suppress CD8+ T Cell Responses Induced by Direct Priming and Cross-Priming and Moderate Immunodominance Disparities. J. Immunol. 174: 3344-3351 [Abstract] [Full Text]  
• He, Y., Zhang, J., Mi, Z., Robbins, P., Falo, L. D. Jr (2005). Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity. J. Immunol. 174: 3808-3817 [Abstract] [Full Text]  
• Yu, P., Lee, Y., Liu, W., Krausz, T., Chong, A., Schreiber, H., Fu, Y.-X. (2005). Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. JEM 201: 779-791 [Abstract] [Full Text]  
• Antony, P. A., Piccirillo, C. A., Akpinarli, A., Finkelstein, S. E., Speiss, P. J., Surman, D. R., Palmer, D. C., Chan, C.-C., Klebanoff, C. A., Overwijk, W. W., Rosenberg, S. A., Restifo, N. P. (2005). CD8+ T Cell Immunity Against a Tumor/Self-Antigen Is Augmented by CD4+ T Helper Cells and Hindered by Naturally Occurring T Regulatory Cells. J. Immunol. 174: 2591-2601 [Abstract] [Full Text]  

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