Intrinsic immune properties of carrier MSC impact on the clinical outcome of children with solid tumors receiving oncolytic virotherapy.
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Our previous clinical data showed that autologous mesenchymal stromal cells (MSCs) can be used as carriers for the systemic delivery of oncolytic adenoviruses in children with advanced cancers, a therapy known as Celyvir. Despite achieving clinical remissions, treatment responses have been heterogeneous. Here, we sought to determine whether intrinsic biological characteristics of carrier MSCs influence therapeutic outcomes. Transcriptomic profiling was performed on MSCs from responder and non-responder patients to identify pathways differentially regulated according to clinical response. Expression of MAVS (mitochondrial antiviral signaling), NF-κB activation, and secretion of pro-inflammatory cytokines were analyzed in MSCs and Celyvir products both at baseline and after adenoviral infection. Among the pathways differentially regulated in MSCs according to treatment response, MAVS was identified as a relevant modulator, showing significantly lower expression in Celyvir products from responder patients. Consistently, MSCs and Celyvir products from responders exhibited reduced NF-κB activation and secreted significantly lower levels of pro-inflammatory cytokines at baseline and post-infection. To validate these findings, immunocompetent mice were treated with murine Celyvir prepared using MAVS-deficient (MAVS-/-) MSCs as a model of "silent cells". Accordingly, murine Celyvir treatment using MAVS-/- MSCs significantly enhanced antitumor efficacy compared to wild-type MSCs. Tumors from animals treated with murine Celyvir MAVS-/- displayed increased infiltration of T cells and NK cells. In summary, carrier MSCs with a diminished antiviral innate immune response-characterized by low MAVS expression and attenuated pro-inflammatory signaling-provide a therapeutic advantage for systemic delivery of oncolytic viruses. These findings support the incorporation of "silent" MSCs, spontaneous or induced, into next-generation clinical trials aiming to optimize cell-based oncolytic virotherapy.