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.
