A compendium of adenovirus genetic modifications for enhanced replication, oncolysis, and tumor immunosurveillance in cancer therapy

doi:10.1016/j.gene.2018.08.069

Gene

Volume 679, 30 December 2018, Pages 11-18

https://doi.org/10.1016/j.gene.2018.08.069 Get rights and content

Highlights

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The mutations in core protein V increase adenovirus replication and progeny yield.
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A downregulation of Dicer and/or RNAi pathway enhances replication and progeny yield.
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The truncation mutations in E3-19K protein increase release of adenovirus progeny.
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A truncation mutation in i-leader sequence increases release of adenovirus progeny.
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The E3-19K protein may be tailored to selectively downregulate only MHCI or MICA/MICB.

Abstract

In this review, we specifically focus on genetic modifications of oncolytic adenovirus 5 (Ad5)-based vectors that enhance replication, oncolysis/spread, and virus-mediated tumor immunosurveillance. The finding of negative regulation of minor core protein V by SUMOylation led to the identification of amino acid residues, which when mutated increase adenovirus replication and progeny yield. Suppression of Dicer and/or RNAi pathway with shRNA or p19 tomato bushy stunt protein also results in significant enhancement of adenovirus replication and progeny yield. Truncation mutations in E3-19K or i-leader sequence or overexpression of adenovirus death protein (ADP) potently increase adenovirus progeny release and spread without affecting virus yield. Moreover, E3-19K protein, which was found to inhibit both major histocompatibility complex I (MHCI) and MHC-I chain-related A and B proteins (MICA/MICB) expression on the cell surface, protecting infected cells from T-lymphocyte and natural killer (NK) cell attack, may be tailored to selectively target only MHCI or MICA/MICB, or to lose the ability to downregulate both. At last, E3-19K protein may be exploited to deliver tumor-associated epitopes directly to the endoplasmic reticulum for loading MHCI in the transporter associated with antigen processing (TAP)-deregulated cells.

Introduction

Human adenovirus 5 (Ad5 together with Ad2 belong to the species C of the family Adenoviridae) is a non-enveloped virus with stable double-stranded linear DNA genome (≈36 kilobase pairs in length), which shows a low rate of spontaneous mutagenesis (1.3 × 10⁻⁷ per base per cell infection cycle) (Risso-Ballester et al., 2016). In the infected cells, the Ad5 genome persists episomally that prevents from adverse insertional mutagenesis inherent to the DNA integrating viruses (Lee et al., 2017). Ad5 can be armed with several therapeutic transgenes, produced and enriched to high titers (1 × 10¹¹–1 × 10¹³ viral particles/ml) (Dobbins et al., 2015; Lee et al., 2017). Ad5-based vectors are well-clinically tested and safe, and have been used in about a quarter of all gene therapy clinical trials (Appaiahgari and Vrati, 2015; Lee et al., 2017). In permissive tumor cells, oncolytic Ad5 infection cycle results in cell lysis (oncolysis) and release of multiple progeny virions, which are able to infect adjacent cells (Barry et al., 2011). In cancer clinical trials, the therapeutic efficacy of oncolytic Ad5-based vectors have been intensively explored (Pesonen et al., 2011; Rosewell Shaw and Suzuki, 2016; Toth and Wold, 2010; Ulasov et al., 2014).

During last two decades, the research community's efforts have been directed at the design of conditionally-replicating adenoviral vectors (replicating mainly in tumor but not normal cells) largely based on serotype 5 with modified tropism (utilization for cell entry of other receptors than its primary native coxsackievirus and adenovirus receptor, CAR), the increased transductional, replicative and lytic efficiency, enhanced intratumoral spread and immune-stimulating properties to overcome the intratumoral radio/chemotherapeutic resistance, phenotypic and genetic heterogeneity and markedly immunosuppressive microenvironment. The genetic and non-genetic approaches to modify Ad5 tropism, increase the transduction efficiency, restrict replication selectively to tumor cells and overcome preexisting antibody-mediated immunity are discussed elsewhere (Alonso-Padilla et al., 2016; Coughlan et al., 2010; Panek et al., 2017; Sonabend et al., 2006; Stepanenko and Chekhonin, 2018; Yoon et al., 2016; Zhang and Ehrhardt, 2017). In this review, we specifically focus on genetic modifications of Ad-based vectors, which were found to enhance replication/progeny yield, oncolysis/spread, and virus-mediated tumor immunosurveillance (Table 1).

Section snippets

Protein V

SUMOylation is a reversible post-translational protein modification, which plays essential roles in many cellular functions. Ad5 modulates the host SUMOylation system. The adenoviral E1B-55K and E4-ORF3 proteins are small ubiquitin-like modifier (SUMO) E3 ligases, inducing SUMOylation of cellular proteins by conjugating SUMO to lysine residues of substrate proteins. Additionally, adenoviral E1A protein associates with the SUMO machinery, while E1B-55K protein itself is a SUMOylation target

The genetic modifications for enhanced adenovirus-mediated tumor immunosurveillance: focus on E3-19K

The mature Ad2 E3-19K protein (without 17 amino acid N-terminal signal sequence) is a transmembrane, endoplasmic reticulum (ER)-localized glycoprotein, consisting of 142 amino acids with a molecular mass of approximately 25 kDa (McSharry et al., 2008; Sester et al., 2010; Sester and Burgert, 1994) (Fig. 1A). E3-19K binds to major histocompatibility complex class I molecules (MHCI/HLA-A/B) and abrogates their transport to the cell surface. E3-19K binds independently both to MHCI and transporter

E3-19K protein

Gros et al. treated wild-type Ad5 with the chemical mutagen nitrous acid (NaNO₂), amplified it in A549 cells and then subjected to various rounds of selection in vivo in nude mice harboring the subcutaneous human pancreatic NP-9 tumors to select mutants with improved oncolytic potency (Gros et al., 2008). An isolated mutant virus was released more efficiently from tested cell lines (CAF1 carcinoma-associated fibroblasts, HEK293 cells, FaDu head and neck cells, SkMel-28 melanoma cells, DLD-1

Conclusion

The current accumulated knowledge on regulation and function of Ad genes and proteins allows designing conditionally-replicating oncolytic viral vectors with enhanced transduction/infectivity (reviewed in (Stepanenko and Chekhonin, 2018)), replication/progeny yield, oncolysis/spread, and virus-mediated antitumor immune responses (Fig. 2). In recent years, the Dicer/RISC-related miRNA-dependent and independent mechanisms of suppression of Ad5 infection have been revealed. Interfering with Dicer

Conflict of interest

The authors have no potential conflict of interest to disclose.

Acknowledgements

The work was financially supported by the Russian Foundation for Basic Research (RFBR), Grant No. 18-29-01009.

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In the case of Ads, the E3/19K protein binds MHC class I molecules in the endoplasmic reticulum, preventing their transport to the plasma membrane, allowing the infection to go undetected.37 Since cancer cells often suppress MHC to prevent the presentation of TAAs,38 deleting the E3/19K gene from OAds can increase MHC class I cell surface expression and enhance tumor immunogenicity.39 However, this could cause an issue whereby immune cells are directed toward the Ad components presented by MHC, rather than TAAs, which may limit the OAd lytic efficacy.
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The cellular internalization (infection of cells) of adenovirus 5 (Ad5) is mediated by the initial attachment of the globular knob domain of the capsid fiber protein to the cell surface coxsackievirus and adenovirus receptor (CAR), then followed by the interaction of the virus penton base proteins with cellular integrins. In tumors, there is a substantial intra- and intertumoral variability in CAR expression. The CAR-negative cells generally exhibit very low infectability. Since the fiber knob is a primary mediator of Ad5 binding to the cell surface, improved infectivity of Ad5-based vectors as oncolytic agents may be achieved via genetic modifications of this domain. The strategies to modify or broaden tropism and increase transduction efficiency of Ad5-based vectors include: 1) an incorporation of a targeting peptide into the fiber knob domain (the HI loop and/or C-terminus); 2) fiber knob serotype switching, or pseudotyping, by constructing chimeric fibers consisting of the knob domain derived from an alternate serotype (e.g., Ad5/3 or Ad5/35 chimeras), which binds to receptor(s) other than CAR (e.g., desmoglein 2/DSG2 and/or CD46); 3) “fiber complex mosaicism”, an approach of combining serotype chimerism with peptide ligand(s) incorporation (e.g., Ad5/3-RGD); 4) “dual fiber mosaicism” by expressing two separate fibers with distinct receptor-binding capabilities on the same viral particle (e.g., Ad5-5/3 or Ad5-5/σ1); 5) fiber xenotyping by replacing the knob and shaft domains of wild-type Ad5 fiber protein with fibritin trimerization domain of T4 bacteriophage or σ1 attachment protein of reovirus. Other genetic approaches to increase the CAR-independent transduction efficiency include insertion of a targeting peptide into the hypervariable region of the capsid protein hexon or fusion to the C-terminus of pIX. Finally, we consider a yet unsolved molecular mechanism of liver targeting by Ad5-based vectors (CAR-, integrin-, fiber shaft KKTK motif-, and hepatic heparan sulfate glycosaminoglycans-independent, but fiber-, hexon- and blood factor X-dependent).

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ReviewA compendium of adenovirus genetic modifications for enhanced replication, oncolysis, and tumor immunosurveillance in cancer therapy

Highlights

Abstract

Introduction

Section snippets

Protein V

The genetic modifications for enhanced adenovirus-mediated tumor immunosurveillance: focus on E3-19K

E3-19K protein

Conclusion

Conflict of interest

Acknowledgements

Adv. Cancer Res.

Mol. Ther.

FEBS Lett.

Mol. Immunol.

J. Biol. Chem.

Mol. Ther. Oncolytics

Genes Dis.

Mol. Ther.

Curr. Opin. Virol.

Gene

Gene

Virology

Genes Dis.

Virus Res.

Virology

Adenoviruses as gene/vaccine delivery vectors: promises and pitfalls

Expert. Opin. Biol. Ther.

Mining the adenovirus “virome” for systemic oncolytics

Curr. Pharm. Biotechnol.

Cutting edge: adenovirus E19 has two mechanisms for affecting class I MHC expression

J. Immunol.

Tropism-modification strategies for targeted gene delivery using adenoviral vectors

Viruses

Truncating the i-leader open reading frame enhances release of human adenovirus type 5 in glioma cells

Virol. J.

A multi targeting conditionally replicating adenovirus displays enhanced oncolysis while maintaining expression of immunotherapeutic agents

PLoS One

Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein

J. Virol.

Sequence arrangement and protein coding capacity of the adenovirus type 2 “i” leader

J. Virol.

HAdV protein V core protein is targeted by the host SUMOylation machinery to limit essential viral functions

J. Virol.

Armed oncolytic viruses: a kick-start for anti-tumor immunity

Cytokine Growth Factor Rev.

Adenovirus release from the infected cell as a key factor for adenovirus oncolysis

Open Gene Ther. J.

Bioselection of a gain of function mutation that enhances adenovirus 5 release and improves its antitumoral potency

Cancer Res.

Arming oncolytic viruses to leverage antitumor immunity

Expert. Opin. Biol. Ther.

Missing or altered self: human NK cell receptors that recognize HLA-C

Immunogenetics

Showing the way: oncolytic adenoviruses as chaperones of immunostimulatory adjuncts

Biomedicine

Presentation of a conserved adenoviral epitope on HLA-C*0702 allows evasion of natural killer but not T cell responses

Viral Immunol.

Increased cytopathic effect of replicating adenovirus expressing adenovirus death protein

Cancer Res. Treat.

MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells

J. Natl. Cancer Inst.

Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation

Nat. Struct. Mol. Biol.

Review
A compendium of adenovirus genetic modifications for enhanced replication, oncolysis, and tumor immunosurveillance in cancer therapy