Adapting a transforming growth factor β–related tumor protection strategy to enhance antitumor immunity

Abstract

Transforming growth factor ␤ (TGF-␤), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. Tumors can avoid the differentiating and apoptotic effects of TGF-␤ by expressing a nonfunctional TGF-␤ receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes (CTLs) from the inhibitory effects of tumor-derived TGF-␤. As our model we used Epstein-Barr virus (

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…Other modifications include the transgenic expression of Th1 cytokines to promote autocrine growth 36,[39][40][41] or the incorporation of a dominant-negative TGF-b receptor, which sequesters this tumor-produced immunosuppressive cytokine. 42,43 Our approach extends upon the dominant-negative receptor concept by inverting a soluble immunosuppressive signal present in the tumor microenvironment into one that is immunostimulatory (4/7 ICR). 44 However, this strategy is not limited to soluble molecules as demonstrated by Jensen and colleagues who designed an inverted receptor to interact with PD-L1 on tumor cells and deliver co-stimulation to transgenic T cells.…”

A strategy for treatment of Epstein–Barr virus-positive Hodgkin's disease by targeting interleukin 12 to the tumor environment using tumor antigen-specific T cells

“…23,24 Briefly, supernatants from the transiently transfected, ecotropic packaging cell line, Phoenix-eco, were used in two rounds of transduction of the packaging cell line PG13 in the presence of polybrene (8 mg/ml) for 48 hours at 321C. Viral supernatants were harvested from the resulting bulk producer lines by adding 20% IMDM to the PG-13 cells and incubated at 321C for 24 hours.…”

“…43,24,14 Prior to retrovirus transduction, CTL were activated on OKT-3 (1 mg/ml; Ortho Pharmaceuticals, Raritan, NJ) and anti-CD28 antibody (1 mg/ml; Pharmingen, San Diego, CA)-coated plates 1 day after the third LCL stimulation. After 24 hours, the CTL were transferred to new noncoated 24-well plates (Costar) at 1 Â 10 6 cells/ml and cultured for another 24 hours in CM supplemented with rIL2 (100 IU/ml) before transduction on non-tissue-culture-treated plates (Becton Dickinson, San Jose, CA), coated with recombinant fibronectin fragment (FN CH-296) (Retronectint, Takara Shuzo, Otsu, Japan) at a concentration of 4 mg/ml, and incubated with equal volumes of freshly generated viral supernatant for 36 hours.…”

“…After 24 hours, the CTL were transferred to new noncoated 24-well plates (Costar) at 1 Â 10 6 cells/ml and cultured for another 24 hours in CM supplemented with rIL2 (100 IU/ml) before transduction on non-tissue-culture-treated plates (Becton Dickinson, San Jose, CA), coated with recombinant fibronectin fragment (FN CH-296) (Retronectint, Takara Shuzo, Otsu, Japan) at a concentration of 4 mg/ml, and incubated with equal volumes of freshly generated viral supernatant for 36 hours. 23,24 As a control, CTL were also transduced with a SFG retrovirus vector encoding the enhanced green fluorescent protein (eGFP). In some experiments, transduced and nontransduced CTL cells were cultured in the presence of recombinant TGFb or IL12 at the concentrations indicated (R&D Systems, Minneapolis, MN).…”

Immunotherapies for Hodgkin's lymphoma

“…Diverse approaches have been investigated preclinically to overcome immune evasion strategies of the tumor and enhance the adoptive immunotherapy of EBV+ HL. Examples include the genetic modification of EBV-CTL to promote resistance to TGF-B [41], to express immunostimulatory cytokines [42], or to express antitumor chimeric T cell receptors [43,44].…”