Sensitivity of human pleural mesothelioma to oncolytic measles virus depends on defects of the type I interferon response

Abstract

Attenuated measles virus (MV) is currently being evaluated as an oncolytic virus in clinical trials and could represent a new therapeutic approach for malignant pleural mesothelioma (MPM). Herein, we screened the sensitivity to MV infection and replication of twenty-two human MPM cell lines and some healthy primary cells. We show that MV replicates in fifteen of the twenty-two MPM cell lines. Despite overexpression of CD46 by a majority of MPM cell lines compared to healthy cells, we found that the sensitivity to MV replication did not correlate with this overexpression. We then evaluated the antiviral type I interferon (IFN) responses of MPM cell lines and healthy cells. We found that healthy cells and the seven insensitive MPM cell lines developed a type I IFN response in presence of the virus, thereby inhibiting replication. In contrast, eleven of the fifteen sensitive MPM cell lines were unable to develop a complete type I IFN response in presence of MV. Finally, we show that addition of type I IFN onto MV sensitive tumor cell lines inhibits replication. These results demonstrate that defects in type I IFN response are frequent in MPM and that MV takes advantage of these defects to exert oncolytic activity.

Oncolytic Viruses—Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer

“…It has also been found that a properly functioning host interferon response pathway is a critical factor in measles infection of malignant pleural mesothelioma. It was seen that in cell lines, there is a correlation between sensitivity of cells to measles infection and an inability of the cell to elicit a full interferon response in the presence of MV ( 138 ). This warrants further investigation as it suggests that inhibition of the interferon pathway could prove to be critical in ensuring the efficiency of oncolytic therapy.…”

A classical PKA inhibitor increases the oncolytic effect of M1 virus via activation of exchange protein directly activated by cAMP 1

“…For instance, intratumoral antiviral response plays a crucial role in blocking the therapeutic spread of oncolytic viruses [16]. Antiviral response is initiated in infected cells after detection of viral RNA by Pattern Recognition Receptors (PRRs) [17].…”

The Susceptibility of Human Melanoma Cells to Infection with the Leningrad-16 Vaccine Strain of Measles Virus

“…There is now evidence that the anti-viral state of the cells likely plays an important role in susceptibility to MV [29]. Indeed, the presence of an intact type I interferon-response pathway in patient tumor samples was shown to correlate strongly with the suppression of MV replication in these cells: the IFN I gene expression level, indicating that the healthy cells and primary tumor cells resistant to virus-mediated oncolysis retained functional antiviral type-I IFN pathways impaired replication of MV, while sensitive cells were defective in these pathways [30,31]. However, other authors reported that melanoma cells retained the ability to release IFN in response to MV infection and were not detrimental to viral killing [10].…”