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 (TGF) secreted by most if not all tumor lesions. Yet TGF also plays critical roles in wound healing, maintenance of epithelial cells, immune cells and neural tissue homeostasis. Thus, inhibitors of TGF have shown limited antitumor activity in clinical trials and many TGF 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 TGF signaling in CD8+ T cells will confer TGF resistance to the T cells while obviating interference with its physiological roles. Previous studies have shown that inhibiting TGF signaling by T cell-specific double-negative TGF receptor (dnTGFRII) 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 TGF signaling in CD8+ T cells using RNA interference to knockdown key mediators in the pathway, will render tumor-specific CD8+ T cells resistant to TGF 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 TGFRII, we are examining whether the inhibition of T cells sensitivity to TGF targeted to CD8+ T cells in vivo is effective at engendering anti- tumor immunity in tumor bearing mice.
Many of the current immunotherapies for cancer exhibit modest therapeutic benefit, highlighting the need to develop more potent or complementary treatments. This limited effect of immune potentiating treatments is mainly orchestrated by the elaborate ways tumors have acquired overtime to prevent their immune-based elimination; therefore, counteracting tumor-associated (derived) immune suppression represents a potential platform for therapeutic intervention. The objective of this proposal is to develop an effective an clinically feasible approach to counteract TGF mediated immune suppression in various cancers.
