Inhibitory RNA molecules in immunotherapy for cancer

Abstract

Over the past few decades, our expanding knowledge of the mammalian immune system - how it is developed, activated, and regulated - has fostered hope that it may be harnessed in the future to successfully treat human cancer. The immune system activated by cancer vaccines may have the unique ability to selectively eradicate tumor cells at multiple sites in the body without inflicting damage on normal tissue. However, progress in the development of cancer vaccines that effectively capitalize on this ability has been limited and slow. The immune system is restrained by complex, negative feedback mechanisms that evolved to protect the host against autoimmunity and may also prevent antitumor immunity. In addition, tumor cells exploit a plethora of strategies to evade detection and elimination by the immune system. For these reasons, the field of cancer immunotherapy has suffered considerable setbacks in the past and faces great challenges at the present time. Some of these challenges may be overcome through the use of RNA interference, a process by which gene expression can be efficiently and specifically "knocked down" in cells. This chapter focuses on the current status and future prospects in the application of small interfering RNA and microRNA, two main forms of RNA interference, to treat cancer by curtailing mechanisms that attenuate the host immune response.

Fig. 1

The processes of siRNA and miRNA-mediated gene silencing. In the miRNA pathway, primary RNA transcripts (pri-miR) are processed by the enzyme Drosha into 60 base pair precursors (pre-miR) in the nucleus. Following export into the cytoplasm, the pre-miR is cleaved into single-stranded 22 nucleotide sequences by the enzyme Dicer and then incorporated into the RISC. The mature miRNA guides the RISC to target mRNA sequences, where it induces either degradation or translational inhibition. The siRNA pathway is similar to the miRNA pathway, with the exception that long, exogenous double-stranded RNA is the initial agent that is processed into a silencing complex

Fig. 2

Immunosuppressive molecules expressed by DCs that can be targeted by RNAi for cancer immunotherapy. A20, SOCS1, and Tyro3/Axl/Mer suppress the antigen presentation and T cell activation capacity of DCs. IDO, PD-L1, DIgR2, Notch ligands, and FasL directly inhibit T cell proliferation, function, or survival. CCL17 and CCL22 mediate the recruitment of T_reg cells to the tumor. miR-155 and miR-146a are predicted to be suppressive miRNAs which inhibit DC function