Abstract
Tumor antigen-reactive T cells must enter into an immunosuppressive tumor microenvironment, continue to produce cytokine and deliver apoptotic death signals to affect tumor regression. Many tumors produce transforming growth factor beta (TGFβ), which inhibits T cell activation, proliferation and cytotoxicity. In a murine model of adoptive cell therapy, we demonstrate that transgenic Pmel-1 CD8 T cells, rendered insensitive to TGFβ by transduction with a TGFβ dominant negative receptor II (DN), were more effective in mediating regression of established B16 melanoma. Smaller numbers of DN Pmel-1 T cells effectively mediated tumor regression and retained the ability to produce interferon-γ in the tumor microenvironment. These results support efforts to incorporate this DN receptor in clinical trials of adoptive cell therapy for cancer.
Highlights
Metastatic melanoma continues to be a therapeutic challenge
Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) or T cell receptor-engineered lymphocytes has produced increased response rates, many clinically dramatic, but most are partial and patients generally relapse within a short time frame [1,2,3]
A remarkable comparison is between spleen and tumorinfiltrating Pmel-1, and the profound suppression of cytokine production in the latter population. These findings suggest that dominant-negative TGFβ receptor II (DN) Pmel are functionally more active within the tumor microenvironment
Summary
Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) or T cell receptor-engineered lymphocytes has produced increased response rates, many clinically dramatic, but most are partial and patients generally relapse within a short time frame [1,2,3]. Factors contributing to these partial responses include down-regulation of MHC and antigen presentation by tumor cells, their resistance to T cell delivered death signals, and tumor production of immunosuppressive factors such as vascular endothelial growth factor (VEGF), Indoleaminepyrrole 2,3-dioxygenase (IDO), IL10 and transforming growth factor-beta (TGFβ) [4,5]. Transgenic mice with TGFβ insensitive T cells are resistant to lymphoma and melanoma tumor challenge [16]
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