Introduction: T-cell lymphomas (TCL) are highly aggressive with poor prognosis and limited treatment options. Epigenetic drugs such as the histone deacetylase inhibitor romidepsin and the DNA methyltransferase inhibitor azacytidine (Romi+AZA) synergize to reprogram tumor gene expression and impact antitumor immunity.
Results: We previously found that Romi+AZA treatment leads to TH1 polarization. Luminex cytokine profiling of Romi+AZA treated PTCL cells found an increased secretion of IFN-γ, GM-CSF and IL-3, suggesting a pro-inflammatory TH1-skewed cytokine environment. RNA-sequencing found strong activation of both IFN-α and IFN-γ axes with dominance of IFN-γ as the key immune effector. This correlated with robust induction of STAT1, Tbx21 and MHC class I/II molecules as well as IFN-γ–responsive effector genes. Functionally, conditioned media (CM) of Romi+AZA treated TCL cells was able to activate T cells isolated from healthy donors and induced CD8+ T-cell-tumor cell killing in co-culture. This T-cell activation and subsequent cytotoxicity was abrogated when IFN-γ was neutralized. Similarly, NK cells stimulated with CM from Romi+AZA-treated TCL cells underwent an increase in proliferation, STAT1 phosphorylation and cytolytic activity, which was lost when IFN-γ was inhibited. Conversely, direct exposure to Romi+AZA did not activate NK cells. Collectively, these findings suggest the indirect activation of T and NK cells through cytokine secretion and not through direct drug-mediated mechanisms.
Conclusion: Romi+AZA treatment leads to remodeling of the PTCL microenvironment, primarily through IFN-γ–driven T and NK cell activation, connecting epigenetic treatment with increased antitumor immunity. The immune-remodeling capacity of Romi+AZA is being evaluated in a TCL in vivo model to test for therapeutic efficacy and microenvironmental reprogramming.
