Immunoregulation and MDSC-Mediated T Cell Paralysis in Hepatocellular Carcinoma Following rVSV-NDV Therapy

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, characterized by a profoundly immunosuppressive tumor microenvironment that hinders effective immune responses. This study evaluates the efficacy of an oncolytic virus therapy in modulating anti-tumor immunity in HCC. Treatment with a recombinant chimeric virus, rVSV-NDV, has been shown to mediate therapeutic effects in preclinical models of HCC, although curative responses were not achieved. Here, we demonstrate robust recruitment of monocytes and effector CD8+T cells into the liver and tumor in response to rVSV-NDV treatment in an HCC mouse model. Subsequent analyses revealed that infiltrating monocytes differentiate into myeloid-derived suppressor cells (MDSCs), coinciding with T cell infiltration and potentially neutralizing their cytotoxic effects. This transition suggests a mechanism of MDSC- mediated inhibition of T cell function within the tumor microenvironment. In vitro studies demonstrated that HCC cells could drive the differentiation of monocytes into MDSCs, which subsequently suppressed T cell activity via methylglyoxal transfer.

To validate the presence and relevance of these cells in vivo we analyzed scRNA-seq datasets from murine HCC models, not only revealing a population of MDSCs but also indicating a potential intermediate state between mononuclear phagocytes and MDSCs. Current investigations focus on elucidating the induction steps and mechanisms driving the differentiation of mononuclear phagocytes into MDSCs, with implications for understanding their role in shaping the immunosuppressive landscape of HCC and identifying potential therapeutic targets. These findings offer insights into the complex interplay between viral therapy and immune suppression, informing future strategies to overcome resistance in immunotherapy.

Publication History

Article published online:
20 January 2025