Abstract
Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure that urgently requires effective therapeutic strategies. Current treatments are unable to increase significantly patient survival, which is often limited to <1 year from diagnosis. Virotherapy, based on the use of oncolytic viruses that exert anti-cancer effects by direct cell lysis and through the induction of anti-tumor immune response, represents an alternative therapeutic option for rare tumors with limited life expectancy. In this study, we propose the use of the adenovirus dl922-947, engineered to allow selective replication in cancer cells, to counteract MPM.Methods: We performed a thorough preclinical assessment of dl922-947 effects in a set of MPM cell lines and xenografts. Cytotoxicity of dl922-947 alone and in combination assays was evaluated by sulforhodamine B assay. Cell cycle, calreticulin expression, and high mobility group box protein 1 (HMGB1) secretion were determined by flow cytometry, whereas ATP content was determined by a luminescence-based bioassay. The modulation of angiogenic factors in MPM-infected cells was evaluated through ELISA.Results: We found that dl922-947 infection exhibits cytotoxic effects in MPM cell lines, affecting cell viability, cell cycle progression, and regulating main hallmarks of immunogenic cell death inducing calreticulin surface exposure, HMGB1 and ATP release. Our results also suggest that dl922-947 may affect angiogenic signals by regulation of VEGF-A and IL-8 secretion. Furthermore, dl922-947 shows anti-tumor efficacy in murine xenograft models reducing tumor growth and enhancing survival. Finally, the combination with cisplatin potentiated the cytotoxic effect of dl922-947.Conclusions: Overall our data identify virotherapy, based on the use of dl922-947, as a new possible therapeutic strategy against MPM, which could be used alone, in combination with standard chemotherapy drugs, as shown here, or other approaches also aimed at enhancing the antitumoral immune response elicited by the virus.
Highlights
Malignant mesothelioma (MM) is an aggressive tumor type with very poor prognosis
To assess whether dl922-947-induced cell death triggers the release of damage-associated molecular pattern molecules (DAMP) and qualifies as immunogenic cell death (ICD), suggesting that the virus can induce the recruitment of immune cells, we evaluated calreticulin exposure, intracellular ATP and High Mobility Group Box Protein 1 (HMGB1) production, the three DAMP hallmarks of ICD [16]
A representative histogram showing the positive control SAHA is reported in Supplemental Figure 2. Overall these findings indicate that dl922-947 is able to induce ICD of malignant pleural mesotheliomas (MPM) cells and through DAMP release, potentially able to trigger a cognate anticancer immune response
Summary
Malignant mesothelioma (MM) is an aggressive tumor type with very poor prognosis. MM is considered a rare cancer, it is estimated that 30,443 new cases will be diagnosed and 25,576 deaths will occur worldwide in 2018 only, contributing importantly to the global cancer burden [1]. The main etiologic factor for MM development is exposure to asbestos, a term that includes six types of carcinogenic mineral fibers that are used commercially [2]. Asbestos use has been banned in many countries, some forms are still mined and used worldwide and other mineral fibers, similar to asbestos, are not even regulated, so there is increasing concern for the development of more MM cases in the future [2]. Malignant pleural mesothelioma (MPM) is an aggressive cancer associated with asbestos exposure that urgently requires effective therapeutic strategies. Virotherapy, based on the use of oncolytic viruses that exert anti-cancer effects by direct cell lysis and through the induction of anti-tumor immune response, represents an alternative therapeutic option for rare tumors with limited life expectancy. We propose the use of the adenovirus dl922947, engineered to allow selective replication in cancer cells, to counteract MPM
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