HDAC inhibitor Chidamide, but not romidepsin, synergizes with humanized PD1 antibody to enhance T-cell chemokine expression and augment IFN-gamma response in NK-T-cell related lymphoma: A preclinical study.

Abstract

e14568 Background: The incidence of NK-T cell lymphoma (NKTL) in Asia is significantly higher than that in European and American countries. The median survival time of EKTL is only 8-12 months, and the 5-year overall survival rate is still less than 30%. New therapies or combinations are warranted. Methods: The murine NKTL cell line EL4 and RMA were used to establish cell line xenograft models in transgenic humanized PD1 mice. Different dosages or sequential HDAC inhibitors were combined with humanized PD1 antibody in vivo to test whether the synergistic effect is existing. RNA-seq, qPCR, and IHC were performed to illustrate the potential mechanisms. Three NTKL patients who were treated with hPD1 and Chidamide in clinical were recorded in this study. Results: Romidepsin combined with hPD1 antibody is superior to hPD1 antibody alone in the treatment of two NKTL CDX models (EL4 and RMA), but it is similar with romidepsin single agent, either in different dosages or sequence. However, Chidamide combined with hPD1 antibody significantly inhibits the tumor growth compared to single agents in these two pre-clinical models. RNA-seq reveals Chidamide synergizes with humanized PD1 antibody to enhance T-cell chemokine expression, augment IFN-gamma response and increase CD8 T cell infiltration. String PPI analysis and ingenuity pathway analysis suggest IFN-gamma is the hub upstream regulator in the combination. On the contrary, the romidepsin combinations decrease the activity of T cell immune responses and the function of immune cell migration. The expression of IFN-gamma gene set signatures is decreased in the romidepsin combination. Three NKTL patients who received PD1 antibody and Chidamide are showed promising efficacy, and the progression-free survival is 26+ months, 8 months, and 9+ months respectively. Conclusions: Different HDAC inhibitor shows different combination effects with immunotherapy. Chidamide combination shows a synergistic effect with immunotherapy by enhancing INF-gamma response, but romidepsin combination antagonizes this effect significantly.