Resistance Mechanisms Influencing Oncolytic Virotherapy, a Systematic Analysis
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Published on: April 3, 2018
Darshak K Bhatt1,2, Roger Chammas2, Toos Daemen1
1University Medical Center Groningen, Department of Medical Microbiology and Infection Prevention, University of Groningen, 9713 AV Groningen, The Netherlands.
Abstract:
Resistance to therapy is a frequently observed phenomenon in the treatment of cancer, and as with other cancer therapeutics, therapies based on oncolytic viruses also face the challenges of resistance, such as humoral and cellular antiviral responses, and tumor-associated interferon-mediated resistance. In order to identify additional mechanisms of resistance that may contribute to therapeutic failure, we developed a systematic search strategy for studies published in PubMed. We analyzed 6143 articles on oncolytic virotherapy and found that approximately 8% of these articles use resistance terms in the abstract and/or title. Of these 439 articles, 87 were original research. Most of the findings reported pertain to resistance mediated by tumor-cell-dependent interferon signaling. Yet, mechanisms such as epigenetic modifications, hypoxia-mediated inhibition, APOBEC-mediated resistance, virus entry barriers, and spatiotemporal restriction to viral spread, although not frequently assessed, were demonstrated to play a major role in resistance. Similarly, our results suggest that the stromal compartment consisting of, but not limited to, myeloid cells, fibroblasts, and epithelial cells requires more study in relation to therapy resistance using oncolytic viruses. Thus, our findings emphasize the need to assess the stromal compartment and to identify novel mechanisms that play an important role in conferring resistance to oncolytic virotherapy.
Insights
Resistance to oncolytic virotherapy is common. This study identified key resistance mechanisms beyond antiviral responses, including tumor-cell-dependent interferon signaling and stromal compartment interactions, crucial for improving cancer treatment outcomes.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Resistance to cancer therapies, including oncolytic virotherapy, is a significant clinical challenge.
- Commonly identified resistance mechanisms include humoral/cellular antiviral responses and interferon-mediated inhibition.
Purpose of the Study:
- To systematically identify and analyze additional resistance mechanisms in oncolytic virotherapy beyond those commonly reported.
- To highlight the role of the tumor microenvironment, specifically the stromal compartment, in therapeutic resistance.
Main Methods:
- A systematic literature search was conducted using PubMed, analyzing 6143 articles on oncolytic virotherapy.
- Articles with 'resistance' in the title or abstract were further filtered for original research (87 articles).
Main Results:
- Approximately 8% of analyzed articles discussed resistance mechanisms.
- Tumor-cell-dependent interferon signaling was the most frequently reported resistance mechanism.
- Other significant, though less frequently assessed, mechanisms include epigenetic modifications, hypoxia, APOBEC, viral entry barriers, and restricted viral spread.
- The stromal compartment (myeloid cells, fibroblasts, epithelial cells) emerged as a critical, understudied factor in resistance.
Conclusions:
- Novel resistance mechanisms beyond antiviral responses play a crucial role in oncolytic virotherapy failure.
- Further investigation into the stromal compartment is essential for understanding and overcoming resistance.
- Identifying these mechanisms is vital for enhancing the efficacy of oncolytic virus-based cancer treatments.
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