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Immunity to Murine Prostatic Tumors: Continuous Provision of T-Cell Help Prevents CD8 T-Cell Tolerance and Activates Tumor-Infiltrating Dendritic Cells

¹ Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program; ² Laboratory of Cell-Mediated Immunity, SAIC-Frederick, Inc.; ³ Biostatistics Division, Data Management Services, National Cancer Institute-Frederick, Frederick, Maryland and ⁴ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Arthur A. Hurwitz, Cancer and Inflammation Program, National Cancer Institute/NIH, 211 Building 567, Frederick, MD 21701. Phone: 301-846-5443; Fax: 301-846-7350; E-mail: hurwitza{at}mail.nih.gov.

Key Words: T cells • Tumor • Immunotherapy • Tolerance • Prostate cancer

We reported previously that tumor-specific CD8⁺ T cells (TcR-I) become tolerant in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. In this study, we show that CD4⁺ TcR transgenic (TcR-II) T cells transferred into TRAMP mice became activated in lymph nodes, trafficked to the prostate, and initially functioned as T_H1 cells. Although a single cotransfer of TcR-II cells delayed TcR-I cell tolerization, repeated transfer of TcR-II cells was required to prevent TcR-I cell tolerization and significantly slowed progression of TRAMP prostate tumors. After transfer of TcR-II cells, dendritic cells within the tumor expressed higher levels of costimulatory molecules and displayed an enhanced ability to stimulate proliferation of naive T cells. Blockade of CD40-CD40L interactions during TcR-II transfer resulted in a profound reduction in dendritic cell stimulatory capacity and a partial loss of TcR-I effector functions and tumor immunity. These data show that sustained provision of activated tumor-specific CD4⁺ T cells alters the immunosuppressive tumor microenvironment, ultimately leading to the control of tumor growth. These findings will assist in the design of more effective immunotherapeutic approaches for cancer. [Cancer Res 2009;69(15):6256–64]

This article has been cited by other articles:

				K. A. Shafer-Weaver, M. J. Anderson, K. Stagliano, A. Malyguine, N. M. Greenberg, and A. A. Hurwitz Cutting Edge: Tumor-Specific CD8+ T Cells Infiltrating Prostatic Tumors Are Induced to Become Suppressor Cells J. Immunol., October 15, 2009; 183(8): 4848 - 4852. [Abstract] [Full Text] [PDF]