Enhancing Antitumor Immunity by Suppressing TGF-Beta Signaling in CD8+ T Cells

University Of Miami School Of Medicine, Coral Gables FL

Investigators

Abstract

? DESCRIPTION (provided by applicant): Cancer immunotherapy is a rapidly developing field aimed at stimulating the immune system that will reverse tumor growth. Current therapies to elicit anti-tumor immune responses are inadequate due to the fact that tumors have elaborated ways to evade immune elimination. A key mediator of immune suppression is the cytokine, transforming growth factor beta (TGFß) secreted by most if not all tumor lesions. Yet TGFß also plays critical roles in wound healing, maintenance of epithelial cells, immune cells and neural tissue homeostasis. Thus, inhibitors of TGFß have shown limited antitumor activity in clinical trials and many TGFß blocking drugs elicited undesirable effects, including immune suppression, due to their broad range of targets and activities. Thus, the underlying premise of our approach, is that specific blockade of TGFß signaling in CD8+ T cells will confer TGFß resistance to the T cells while obviating interference with its physiological roles. Previous studies have shown that inhibiting TGFß signaling by T cell-specific double-negative TGFß receptor (dnTGFßRII) expression led to enhanced immune responses against transplantable tumors in murine models. With the goal of developing a more clinically feasible approach, we hypothesized that inhibition of TGFß signaling in CD8+ T cells using RNA interference to knockdown key mediators in the pathway, will render tumor-specific CD8+ T cells resistant to TGFß suppression. The siRNAs will be targeted to the T cells in vivo by conjugation to a targeting aptamer ligand. Aptamers are single-stranded oligonucleotides selected to bind a specific target of interest with affinity and avidity comparable to, if not superior to that of monoclonal antibodies. Using an aptamer against the costimulatory molecule 4-1BB, transiently upregulated on activated CD8+ T cells, conjugated to siRNA against SMAD4 and TGFßRII, we are examining whether the inhibition of T cells sensitivity to TGFß targeted to CD8+ T cells in vivo is effective at engendering anti- tumor immunity in tumor bearing mice.