Oncolytic virotherapy targets IFN-unresponsive melanoma cells, but dedifferentiation limits efficacy post-immunotherapy.

Resistance to immune checkpoint inhibitor (ICI) therapy in melanoma often arises from tumor cells evolving to evade immune surveillance. A key mechanism involves genetic mutations disrupting interferon (IFN) signaling, which allows cancer cells to escape T cell-mediated immunity. However, this loss of IFN signaling might also render these cells uniquely susceptible to oncolytic viruses, which rely on intact host IFN pathways for their replication and spread. Understanding these paradoxical roles of cancer cell-intrinsic IFN signaling is crucial for developing effective combination therapies and overcoming resistance.

Researchers generated IFN-unresponsive mouse melanoma cell variants using CRISPR/Cas9 technology. These cells, along with wild-type melanoma cells, were transplanted into immunocompetent syngeneic hosts (mice). The study investigated the impact of sequential immuno-virotherapy on tumor evolutionary dynamics. Experiments included groups with NK cell depletion to observe the selection of IFN-unresponsive subclones. The primary endpoint was the fate and re-emergence of different tumor cell phenotypes under sequential treatment with T cell-directed immunotherapy followed by oncolytic virotherapy.

In wild-type mice, Natural Killer (NK) cells effectively eliminated IFN-unresponsive subclones in mixed tumor cell transplants due to their very low expression of major histocompatibility complex class I (MHC-I) molecules. However, upon NK cell depletion, IFN-unresponsive subclones successfully established and were preferentially selected by T cell-directed immunotherapy, mirroring observations in human patients. Sequential oncolytic virotherapy was then able to specifically target and counter-select these IFN-unresponsive clones, demonstrating its potential to overcome ICI resistance. > Unexpectedly, during this sequential treatment, IFN-responsive tumor cells re-emerged with a dedifferentiated phenotype that exhibited resistance to both immune and viral control. This dedifferentiation ultimately limited the overall efficacy of the combined treatment approaches.