期刊
JOURNAL OF IMMUNOLOGY
卷 191, 期 6, 页码 3232-3239出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1301270
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资金
- Dutch Cancer Society [2009-4282]
- Leukaemia and Lymphoma Research Bennett Senior Nonclinical Fellowship [12004]
TCR gene therapy is a promising approach for the treatment of various human malignancies. However, the tumoricidal activity of TCR-modified T cells may be limited by local immunosuppressive mechanisms within the tumor environment. In particular, many malignancies induce T cell suppression in their microenvironment by TGF-beta secretion. In this study, we evaluate whether blockade of TGF-beta signaling in TCR-modified T cells enhances TCR gene therapy efficacy in an autochthonous mouse tumor model. Treatment of mice with advanced prostate cancer with T cells genetically engineered to express a tumor-reactive TCR and a dominant-negative TGF-beta receptor II induces complete and sustained tumor regression, enhances survival, and leads to restored differentiation of prostate epithelium. These data demonstrate the potential to tailor the activity of TCR-modified T cells by additional genetic modification and provide a strong rationale for the clinical testing of TGF-beta signaling blockade to enhance TCR gene therapy against advanced cancers.
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