T Cell Surveillance of Oncogene-Induced Prostate Cancer Is Impeded by T Cell-Derived TGF-β1 Cytokine

• Published in: Immunity (Cambridge, Mass.) Vol. 35; no. 1; pp. 123 - 134
• Main Authors: Donkor, Moses K., Sarkar, Abira, Savage, Peter A., Franklin, Ruth A., Johnson, Linda K., Jungbluth, Achim A., Allison, James P., Li, Ming O.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.07.2011
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - pathology; Animals; Cell Growth Processes - genetics; Cell Growth Processes - immunology; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Disease Models, Animal; Humans; Immune Tolerance; Immunologic Surveillance; Lymphocyte Depletion; Male; Mice; Mice, Transgenic; Oncogenes - physiology; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Receptors, Antigen, T-Cell - genetics; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - pathology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism; Tumor Escape
• ISSN: 1074-7613; 1097-4180; 1097-4180
• DOI: 10.1016/j.immuni.2011.04.019

Tolerance induction in T cells takes place in most tumors and is thought to account for tumor evasion from immune eradication. Production of the cytokine TGF-β is implicated in immunosuppression, but the cellular mechanism by which TGF-β induces T cell dysfunction remains unclear. With a transgenic model of prostate cancer, we showed that tumor development was not suppressed by the adaptive immune system, which was associated with heightened TGF-β signaling in T cells from the tumor-draining lymph nodes. Blockade of TGF-β signaling in T cells enhanced tumor antigen-specific T cell responses and inhibited tumor development. Surprisingly, T cell- but not Treg cell-specific ablation of TGF-β1 was sufficient to augment T cell cytotoxic activity and blocked tumor growth and metastases. These findings reveal that T cell production of TGF-β1 is an essential requirement for tumors to evade immunosurveillance independent of TGF-β produced by tumors. ► The adaptive immunity does not protect against TRAMP tumor development ► Lack of protective immunity is associated with enhanced TGF-β signaling in T cells ► Blockade of TGF-β signaling in T cells protects TRAMP mice from tumor development ► T cell-specific deletion of TGF-β1 is sufficient to break tumor T cell tolerance