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Review
. 2020 Sep 9;9(9):2061.
doi: 10.3390/cells9092061.

Nucleic Acid-Based Approaches for Tumor Therapy

Simone Hager  1 , Frederic Julien Fittler  2 , Ernst Wagner  1 , Matthias Bros  2
Affiliations
Review

Nucleic Acid-Based Approaches for Tumor Therapy

Simone Hager et al. Cells. .

Abstract

Within the last decade, the introduction of checkpoint inhibitors proposed to boost the patients' anti-tumor immune response has proven the efficacy of immunotherapeutic approaches for tumor therapy. Furthermore, especially in the context of the development of biocompatible, cell type targeting nano-carriers, nucleic acid-based drugs aimed to initiate and to enhance anti-tumor responses have come of age. This review intends to provide a comprehensive overview of the current state of the therapeutic use of nucleic acids for cancer treatment on various levels, comprising (i) mRNA and DNA-based vaccines to be expressed by antigen presenting cells evoking sustained anti-tumor T cell responses, (ii) molecular adjuvants, (iii) strategies to inhibit/reprogram tumor-induced regulatory immune cells e.g., by RNA interference (RNAi), (iv) genetically tailored T cells and natural killer cells to directly recognize tumor antigens, and (v) killing of tumor cells, and reprograming of constituents of the tumor microenvironment by gene transfer and RNAi. Aside from further improvements of individual nucleic acid-based drugs, the major perspective for successful cancer therapy will be combination treatments employing conventional regimens as well as immunotherapeutics like checkpoint inhibitors and nucleic acid-based drugs, each acting on several levels to adequately counter-act tumor immune evasion.

Keywords: adjuvant; antigen; dendritic cell; immunotherapy; nanoparticle; nucleic acids; transgene; tumor.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Nucleic acid-based strategies for tumor therapy. Vaccination of dendritic cells (DC) aims to induce tumor-specific effector T cells (Teff), which in turn kill tumor cells. Regulatory immune cells, regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), are induced by the tumor and other cells of the tumor microenvironment (TEM) and inhibit both DC and Teff. The expansion and suppressive activity of Treg/MDSC can be inhibited by RNA interference (RNAi) and MDSC may be reprogramed to yield antigen presenting cells by applying nucleic acid-based stimuli. Further, T cells can be transfected/transduced with chimeric antigen receptors (CAR) to gain tumor specificity. Teff are inhibited by factors within the TME. Tumor-specific delivery of nucleic acids (gene-coding or conferring RNAi) is aimed to induce apoptosis in tumor cells, and to inhibit or reprogram accessory cells within the TME, tumor-associated macrophages (TAM), and cancer-associated fibroblasts (CAF).
Figure 2
Figure 2
Mechanism of RNA interference (RNAi) and options for therapeutic intervention. (1) Substitution of tumor suppressor micro-RNA (miRNA, miR) in form of pre-miRNA or miRNA mimics, thereby inducing RNAi. (2) Blocking of oncogenic miRNA by miRNA-specific antagomirs (anti-miR). This figure is reprinted with permission from [103]. Copyright © 2020; John Wiley and Sons.
Figure 3
Figure 3
Immune checkpoint inhibition mediated by nucleic acid-based strategies. (a) Besides recognition of major histocompatibility complex (MHC)-bound antigen on the surface of APC via TCR, co-stimulatory signals—inter alia interaction of CD80 (B7-1) and CD28—are required for full T cell activation. The duration and intensity of activation is regulated among other things by immune checkpoint CTLA-4 that binds with high affinity to CD80. Blocking of this interaction results in enhanced T cell activity. One therapeutic option is delivery of mRNA encoding for anti-CTLA-4 antibodies. (b) Tumor cells often upregulate PD-L1 that binds to PD-1 on effector T cells, thereby inhibiting the activity of effector T cells. Nucleic acid-based approaches for blocking this immune checkpoint comprise siRNA against PD-L1, pDNA encoding for PD-L1 trap proteins (pPD-L1-trap), and CRISPR/Cas9-mediated knock-down of PD-1 gene.
Figure 4
Figure 4
Genetic modifications to enhance selectivity, safety, and efficacy of oncolytic virotherapies.
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