Poster Presentation 29th Lorne Cancer Conference 2017

Modulation of PD-1 and PD-L1 expression in myeloid malignancies: Evidence for potential biomarker evaluation of resistance to epigenetic therapy (#207)

Hongbin Liu 1 , Yunshan Hu 1 , Rafael P Rimoldi 1 , Nora Lee 2 , Shaun Fleming 3 4 , Andrew Spencer 3 4 , Anthony E Dear 1 4
  1. Medicine, Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
  2. Haematology, Eastern Health, Melbourne, Victoria, Australia
  3. Haematology, Alfred Hospital, Melbourne, Victoria, Australia
  4. Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia

Immune checkpoint inhibition has emerged as a novel and effective therapy in the treatment of solid tumours and haematological malignancies1. Recent evidence in myeloid malignancies suggests epigenetic therapy regulates expression of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) and may correlate with emergence of treatment resistance2. 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.

Our study aimed to evaluate the in vitro and in vivo effects of EGT on expression of PD-1 and PD-L1 in order to characterise the potential utility of these molecules as biomarkers of resistance to EGT. Analysis of PD-1 and PD-L1 mRNA expression in KG-1 leukemia cells treated with either the demethylating agent azacytidine (AZA) or the histone deacetylase inhibitors (HDACi) MCT-3 or LBH-589 or a combination of these agents demonstrated significant induction of PD-1 and PD-L1 expression with either single agent or combination EGT. PD-1 and PD-L1 mRNA expression was also analysed in peripheral blood mononuclear cell (PBMC) samples from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients treated with either AZA alone or a combination of AZA and the HDACi LBH5895. Early in vivo modulation of PD-1 and PD-L1 mRNA expression was identified in patient samples in response to EGT.

Together these observations suggest that the in vitro and in vivo expression of PD-1 and PD-L1 are modulated in response to single and dual agent EGT in MDS/AML. Our ongoing studies aim to validate the clinical significance of these observations and will inform on the potential use of PD-1 and PD-L1 as biomarkers of resistance to EGT in myeloid malignancies and the possible role of immune checkpoint inhibitor therapy in this setting.

  1. Trivedi MS, Hoffner B, Winkelmann JL et al. Programmed death 1 immune checkpoint inhibitors. Clin Adv Hematol Oncol. 13:858-68 (2015).
  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. 2016 Dec 1. doi: 10.1111/bjh.14463. [Epub ahead of print].
  5. Tan P, Wei A, Mithraprabhu S et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J.10;4:e170 (2014).