W.SIM1, W.M.LIM1, L.W.HII1, S.F.WONG1, C.O.LEONG1
International Medical University1
Pancreatic Ductal Adenocarcinoma (PDAC) ranks among the deadliest malignancies and is refractory to most treatments including surgery, radiotherapy and chemotherapy. Immunotherapies using Cytotoxic T Lymphocytes (CTLs) to eliminate PDAC represents a promising strategy but efforts to maximise immunotherapy have been limited by CTL-mediated cytotoxicity resistance (CTLR). The objective of the study is to determine whether Histone Deacetylase Inhibitors (HDACi) can overcome CTLR thus allowing the harnessing of immunotherapy for PDAC treatment.
BXPC3 and SW1990 parental and CTL-resistant cell lines were treated with HDACi (Belinostat, Givinostat, Vorinostat) at 10μM and CTLs at different ratios (CTLs: PDAC ratios of 1:1, 2:1, 4:1, 8:1, 16:1). To compare with conventional cytotoxic drugs used in PDAC treatment, gemcitabine and 5-fluorouracil were included in the assay. Cell viability was measured using CellTiter-Glo Luminescent Assay.
HDACi use showed successful reversal of CTLR in BXPC3 and SW1990 CTL-resistant cell lines. Further, HDACi increased sensitivity of PDAC cells towards CTLs across all cell lines. In BXPC3 and SW1990 CTL-resistant cell lines, Givinostat caused the greatest improvement in CTL sensitivity with approximately 80% reduction in cell viability. The results also demonstrated that current chemotherapeutic drugs used in PDAC treatment including gemcitabine and 5-fluorouracil do not increase PDAC sensitivity to CTLs nor cause reversal of CTLR.
The results of this study support the utilisation of HDACi in combination with conventional immunotherapeutic drugs to overcome potential CTLR. Even when CTLR is absent, the inclusion of HDACi is favoured as HDACi can sensitize PDAC towards CTLs and enhance CTL-mediated killing.