Nucleic Acid Immunotherapeutics for Cancer

Abstract

The past decade has witnessed the blossom of two fields: nucleic acid therapeutics and cancer immunotherapy. Unlike traditional small molecule medicines or protein biologics, nucleic acid therapeutics have characteristic features such as storing genetic information, immunomodulation, and easy conformational recovery. Immunotherapy uses the patients' own immune system to treat cancer. A variety of strategies have been developed for cancer immunotherapy including immune checkpoint blockade, adoptive cell transfer therapy, therapeutic vaccines, and oncolytic virotherapy. Interestingly, nucleic acid therapeutics have emerged as a pivotal class of regimen for cancer immunotherapy. Examples of such nucleic acid immunotherapeutics include immunostimulatory DNA/RNA, mRNA/plasmids that can be translated into immunotherapeutic proteins/peptides, and genome-editing nucleic acids. Like many other therapeutic nucleic acids, nucleic acid immunotherapeutics often require chemical modifications to protect them from enzymatic degradation and need drug delivery systems for optimal delivery to target tissues and cells and subcellular locations. In this review, we attempted to summarize recent advancement in the interfacial field of nucleic acid immunotherapeutics for cancer treatment.

Keywords: adjuvant; cancer; immunotherapy; nucleic acid therapeutics; vaccine.

Figure 1.

Schematic depiction of common nucleic acid therapeutics for cancer immunotherapy. Immunostimulatory (IS) nucleic acids of PAMPs are detected by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) on the endosome membrane and cyclic GMP-AMP synthase (cGAS) in the cytosol that culminate in the production of type I interferons (IFNs) and proinflammatory cytokines, leading to the promotion of anticancer immune responses. Moreover, genetic carriers such as plasmids and mRNA can express functional RNA or protein/peptides that promote anticancer immune responses. Gene-regulating nucleic acids, such as siRNA/shRNA, gene activating nucleic acids, antisense oligonucleotides, and gene-editing nucleic acids, can regulate immune-related genes for the activation of anticancer immune responses. Other nucleic acids such as aptamers can function as agonists or antagonists against immune-related molecular targets so as to promote anticancer immune responses. For cancer immunotherapy, these nucleic acid immunotherapeutics can be engineered to function in a wide variety of cells including antigen-presenting cells (APCs), T cells or natural killing (NK) cells, and cancer cells. dsDNA, double-stranded DNA; dsRNA, double-stranded RNA; STING, stimulator of interferon genes; cGAS, cyclic GMP-AMP synthase; TBK1, TANK-binding kinase 1; Stat6, signal transducer and activator of transcription 6; IRF3, interferon regulatory factor 3; IKK, IκB kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; TLR, Toll-like receptors; TRIF, TIR-domain-containing adapter-inducing interferon-β (TRIF); MHC, major histocompatibility complex; GM-CSF, granulocyte-macrophage colony-stimulating factor; CARs, chimeric antigen receptors; CDNs, cyclic dinucleotides; TAA, tumorassociated antigen.

Figure 2.

Overview of nucleic acid immunotherapeutics that can activate the cGAS-STING signaling pathway. CDNs activate STING to produce type I IFNs that can be leveraged for cancer immunotherapy. Adapted with permission from ref . Copyright (2013) Elsevier Publishing Group.

Figure 3.

Schematic depiction of mRNA vaccines for cancer immunotherapy. Note that, by using MHC-I or MHC-II-restricted antigens that are translated from mRNA vaccines, both arms of CD8⁺ and CD4⁺ T cell responses, respectively, can be elicited or augmented. Adapted with permission from ref . Copyright (2013) Elsevier Publishing Group.

Figure 4.

Nonviral delivery of CRISPR-Cas9 system for gene editing. Cas9 ribonuclease can be delivered in the forms of Cas9-expressing DNA, Cas9-expressing mRNA, and Cas9 protein. sgRNA can be delivered by expression from sgRNA-coding DNA or as independent oligonucleotides together with Cas9-expressing mRNA or Cas9 proteins. Adapted with permission from ref . Copyright (2017) American Chemical Society Publishing Group.

Figure 5.

Versatile chemical modifications that can improve the biostability, pharmacokinetics and pharmacodynamics, and immunogenicity of nucleic acids therapeutics. These modifications can be at the 5′- or 3′-terminals, the phosphodiester linkage, on the sugar rings, or on the bases. Adapted with permission from ref . Copyright (2017) MDPI Publication.