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Updated: May 4, 2026
Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy
Published on: April 3, 2018
STAT1 interaction with E3-14.7K in monocytes affects the efficacy of oncolytic adenovirus
Emma Spurrell1, Rathi Gangeswaran, Pengju Wang
1Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
Abstract:
Oncolytic viruses based on adenovirus type 5 (Ad5) have been developed as a new class of therapeutic agents for cancers that are resistant to conventional therapies. Clinical experience shows that these agents are safe, but virotherapy alone has not achieved long-term cure in cancer patients. The vast majority of oncolytic adenoviruses used in clinical trials to date have deletion of the E3B genes. It has been demonstrated that the antitumor potency of the E3B-deleted mutant (dl309) is inferior to adenovirus with E3B genes intact. Tumors treated with dl309 show markedly greater macrophage infiltration than E3B-intact adenovirus. However, the functional mechanisms for this were not previously known. Here, we demonstrate that deletion of E3B genes increases production of chemokines by monocytes after adenovirus infection and increases monocyte migration. The E3B 14,700-Da protein (E3B-14.7K) inhibits STAT1 function by preventing its phosphorylation and nuclear translocation. The STAT1 inhibitor, fludarabine, rescues the effect of E3B-14.7K deletion by downregulating target chemokine expression in human and murine monocytes and results in an enhanced antitumor efficacy with dl309 in vivo. These findings have important implications for clinical use of E3B-deleted oncolytic adenovirus and other E3B-deleted adenovirus vector-based therapy.
Insights
E3B gene deletion in oncolytic adenoviruses increases chemokine production and monocyte migration, reducing antitumor efficacy. Restoring STAT1 function enhances therapeutic potential for cancer treatment.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Adenovirus research
Background:
- Oncolytic adenoviruses are promising cancer therapies but often lack E3B genes.
- E3B-deleted adenoviruses show reduced antitumor potency compared to E3B-intact counterparts.
- Increased macrophage infiltration is observed in tumors treated with E3B-deleted adenoviruses.
Purpose of the Study:
- To elucidate the functional mechanisms behind the reduced efficacy of E3B-deleted oncolytic adenoviruses.
- To investigate the role of E3B genes in adenovirus-mediated immune responses.
- To explore strategies for enhancing the therapeutic potential of E3B-deleted adenoviruses.
Main Methods:
- Adenovirus infection of human and murine monocytes.
- Measurement of chemokine production and monocyte migration.
- Analysis of STAT1 phosphorylation and nuclear translocation.
- In vivo studies using E3B-deleted adenovirus and STAT1 inhibitor.
Main Results:
- Deletion of E3B genes in adenovirus enhances monocyte chemokine production and migration.
- The E3B 14,700-Da protein inhibits STAT1 phosphorylation and nuclear translocation.
- STAT1 inhibition by E3B-14.7K is reversed by fludarabine, reducing chemokine expression.
- Combined treatment with E3B-deleted adenovirus and fludarabine improved antitumor efficacy in vivo.
Conclusions:
- E3B gene deletion in oncolytic adenoviruses impairs antitumor efficacy by promoting pro-inflammatory monocyte responses.
- The E3B-14.7K protein plays a crucial role in regulating STAT1-mediated chemokine production.
- Targeting STAT1 offers a potential strategy to enhance the clinical effectiveness of E3B-deleted oncolytic adenoviruses.
