The Combination Treatment of Romidepsin and Azacytidine Modifies the Immune Landscape in Models of T-Cell Lymphoma

Introduction: T-cell lymphomas (TCL) is a rare and aggressive form of non-Hodgkin's lymphoma characterized by the malignant proliferation of T-cells. Despite recent advances in understanding the disease biology and development of novel therapies, PTCL remains a challenging clinical entity. 

Results: In this study, we investigated the effects of the histone deacetylase inhibitor (HDACi) romidepsin and the DNA methyltransferase inhibitor (DNMTi) azacytidine on the immune landscape of TCL. Our findings demonstrate that the combination of romidepsin and azacytidine induces a T-Helper-1, TH1-dominant phenotype in TCL cells in vitro, as evidenced by the upregulation of key transcription factor Tbx21 and the TH1-chemokine receptor CXCR3, activation of the downstream STAT1/STAT4 signaling and elevated levels of the TH1 cytokine IFN-γ. Moreover, luminex cytokine profiling further revealed the increase in the pro-inflammatory cytokines GM-CSF and IL-3 detected in the supernatants of TCL cells treated with the drug combination, indicative of M1 macrophage activation and possible other immune cell types within the tumor microenvironment.

Importantly, conditioned media from TCL cell lines treated with the drug combination was able to induce TH1 polarization of activated T-cells isolated from the peripheral blood of health donors and a significant T-cell-mediated killing of TCL cells in an in vitro co-culture system. This suggests that release of soluble factors from treated malignant cells can reprogram the tumor microenvironment.

Conclusion: These findings are being further explored in additional TCL subtypes and a syngeneic mouse model to assess the potential of this combination therapy to convert the tumor microenvironment from a cold to a hot state.