Induction of Tumor Immunity by Targeted Inhibition of Nonsense-mediated mRNA Decay

Abstract

Whereas tumor progression in cancer patients can elicit a weak immune response which keeps the tumor in check, albeit transiently, the weak antigenicity of the tumor provides the time and opportunity for the tumor to elaborate immune evasion mechanisms. Weak antigenicity is, therefore, the root cause why tumors escape immune control. We have recently described a way to activate the antitumor immune response that is fundamentally different from current strategies collectively referred to as "cancer vaccination," because instead of stimulating immune responses against existing and mostly weak, tumor antigens, novel, and thereby potent, antigens are induced de novo in the disseminated tumor lesions of the patient. The approach is to inhibit a process in the tumor cells known as nonsense-mediated mRNA decay (NMD). The physiological role of NMD is to eliminate defective products generated in the cells, and therefore inhibiting the NMD process will lead to the accumulation of defective products, some of which will encode novel, and thereby potent, antigens to which the immune system has not been tolerized. Inhibition of NMD was accomplished using chemically synthesized siRNAs to downregulate key mediators of the NMD process such as Smg-1 or Upf-2. However, since NMD is a constitutive process that operates in all the somatic cells of the body, global inhibition of NMD could lead to system-wide autoimmune pathology. To obviate the risk of autoimmunity, NMD inhibition was limited to the disseminated tumor lesions by targeted delivery of siRNAs conjugated to oligonucleotide aptamer ligands that bind to receptors expressed preferentially, if not exclusively, on the tumor cells. We have shown that in subcutaneous and metastatic murine tumor models, the tumortargeted delivery of NMD factor siRNAs led to signifi cant inhibition of tumor growth which was superior to that of a gold standard "conventional" cancer vaccination protocol. Tumor-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumors leading to their immune recognition and rejection. The cellfree chemically synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.