Poster Presentation 30th Lorne Cancer Conference 2018

Epigenetic treatment-mediated modulation of PD-L1 predicts potential therapy resistance over response markers in myeloid malignancies: A molecular mechanism involving effectors of PD-L1 reverse signalling (#209)

Hongbin Liu , Yunshan Hu , Rafael Rimoldi , Chloe Von Hagt , Nora Lee , Shaun Fleming , Andrew Spencer , Anthony Dear

Immune checkpoint inhibition has emerged as a novel and effective therapy in the treatment of solid tumours and haematological malignancies1. Recent evidence has suggested a correlation between resistance to epigenetic therapy (EGT) and the expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) in myeloid malignancies2. Despite identification of several putative markers of early response to epigenetic therapy (EGT)3,4 characterisation of biomarkers to predict emergence of resistance to EGT in myeloid malignancies are required together with delineation of associated molecular mechanisms which may subsequently inform on novel treatment strategies in the setting of resistance to EGT. Our study aimed to correlate the in vivo effects of EGT on expression of PD-1, PD-L1 and orphan nuclear receptor NUR77 with clinical response in patients with myeloid malignancies. In addition, in vitro and in vivo characterisation of the effects of EGT on NF-кB and Bcl-xL expression, potential downstream targets of PD-L1 reverse signalling5, was evaluated to delineate possible components of the molecular mechanism responsible for these effects.

The in-vivo effects of EGT on expression of PD-1, PD-L1 and a previously identified molecular marker of response to EGT, orphan nuclear receptor NUR77 was characterised in peripheral blood mononuclear cells (PBMC) from patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) treated with either azacytidine (AZA) alone or a combination of AZA and the histone deacetylase inhibitor (HDACi) LBH589 during the first cycle of therapy. Correlation of clinical response to EGT treatment with expression of PD-1, PD-L1 and NUR77 demonstrated induction of PD-L1 mRNA levels was associated with resistance to EGT despite concurrent augmentation of NUR77 expression. Determination of expression of potential downstream effector molecules of PD-L1 reverse signalling identified EGT-mediated induction of Bcl-xL and NFκB mRNA expression both in-vitro and in-vivo suggesting a potential anti-apoptotic molecular mechanism responsible for PD-L1-mediated resistance to EGT.

Together these observations suggest enhanced PD-L1 expression may herald resistance to EGT over known markers of response to EGT in myeloid malignancies and provide a potential molecular mechanism involving modulation of effectors of PD-L1 reverse signalling which may, in-part, be responsible for these effects.

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  2. Yang H, Bueso-Ramos C, DiNardo C et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 28:1280-8 (2014).
  3. Liu HB, Urbanavicius D, Tan P, Spencer A, Dear AE. Mechanisms and potential molecular markers of early response to combination epigenetic therapy in patients with myeloid malignancies. Int J Oncol. 45:1742-8 (2014).
  4. Lübbert M, Ihorst G, Sander PN et al. Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5-aza-2'-deoxycytidine (Decitabine). Br J Haematol. 176:609-17 (2016).
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