Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses

Therapy-induced senescence (TIS) as a permanent growth arrest can be induced by various stimuli, including anticancer compounds. TIS emerged as a promising strategy to overcome resistance phenomena. However, senescent cancer cells might regain proliferation activity in vivo or even secrete tumor-promoting cytokines. Therefore, successful exploitation of TIS in cancer treatment simultaneously requires the development of effective strategies to eliminate senescent cancer cells. Virotherapy aims to selectively hit tumor cells, thus a combination with senescence-inducing drugs was explored. As a model, we chose measles vaccine virus (MeV), which does not interfere with cellular senescence by itself. In different tumor cell types, such as hepatoma, pancreatic and mammary gland carcinoma, we demonstrate efficient viral replication and lysis after TIS by gemcitabine, doxorubicin or taxol. Applying real time imaging, we even found an accelerated lysis of senescent cancer cells, supporting an enhanced viral replication with an increase in cell-associated and released infectious MeV particles. In summary, we show as a proof-of-concept that senescent tumor cells can be efficiently exploited as virus host cells by oncolytic MeV. These observations open up a new field for preclinical and clinical research to further investigate TIS and oncolytic viruses as an attractive combinatorial future treatment approach. What's new? Therapeutic induction of senescence (TIS) has emerged as a promising cancer treatment strategy with the potential to overcome therapy resistance due to the ability of tumor cells to evade apoptosis. Although senescent cells undergo a permanent cell cycle arrest, they remain metabolically active in vivo, making combination approaches to eliminate them urgently needed. This study provides a proof-of-concept that, despite the profoundly altered phenotype of senescent tumor cells, oncolytic viruses are able to hijack cancer cells after TIS, leading to a destruction of tumor cells. These observations open up a new research field at the crossroads between TIS and virotherapy.