Immune evasion is a hallmark of persistence and progression of many haematological and non-haematological tumors. Progression of acute myeloid leukaemia (AML) post allogeneic stem cell transplant is often associated with evidence of immune escape and relapse in immuno-privileged sites. Natural killer (NK) cells play a key role in the control of malignancy and have been implicated in the success of haplo-identical allogeneic transplantation for AML. It is not known whether expression of NK cell-activating ligands on AML blasts may allow for improved immunological surveillance in the absence of allogeneic transplant following remission induction and therefore predict a lower rate of relapse in these high-risk patients.
A pilot study of 19 AML patients undertaken by our group and others identified that patients with intermediate/high blast expression of activating NK ligands MIC A and B, CD155 and ULBP1,2,5 and 6 correlated with favourable cytogenetics and a lower incidence of leukaemia-specific mortality, compared to those with low to nil expression.
We further assessed the impact of NK ligand (CD112 and CD155, HLA-A/B/C, PD-L1 and PD-L2, MIC A and B, ULBP1,2,5 and 6) expression on prognosis in AML on a larger cohort. Bone marrow aspirates from 63 newly diagnosed patients who received intensive cytarabine based remission induction chemotherapy were evaluated by 14 colour flow cytometry on a BD LSR Fortessa for expression of 4 activating and 6 inhibitory ligands. Blasts were identified by size, granularity and expression of CD45 according to diagnostic flow cytometry gating procedures. The number and net phenotype (inhibitory vs activating) of ligand expression was compared with both overall survival (OS) and relapse free survival (RFS).
The median age of the cohort was 53.7 years, with a median bone marrow blast count of 71% at diagnosis. 73% of patients had intermediate risk cytogenetics (as defined by the MRC classification), 19% were poor risk, with only 8% having a favourable cytogenetic profile. Median survival was 19.3 months and correlated closely with cytogenetic risk group. MIC A and B, ULBP1,2,5 and 6, all recognized by the NK cell activating receptor NKG2D, were found to be the most prevalent on AML blasts, with 50% of patients expressing one or more of these ligands. However the intensity and combinatorial expression of these markers varied extensively between patients. Interim survival analysis showed a trend towards increased OS in patients having a net activating ligand phenotype compared to those with a balanced or an inhibitory phenotype. This difference was more pronounced in the subset of patients with intermediate risk cytogenetics. Further subgroup and single ligand analyses are underway.
As well as highlighting the essential role that NK cells play in modulating the anti-tumour immune response, this preliminary data also suggests that expression of NK cell ligands on the surface of AML blasts at diagnosis may correlate with overall survival and become a promising biomarker for patient outcome in AML.
Citation Format: Rachel Koldej, Jane Ripley, Christopher Chan, Mark Smyth, Paul Neeson, David Ritchie, Travis Perera. Prognostic significance of natural killer ligand expression in acute myeloid leukemia. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A019.
- ©2016 American Association for Cancer Research.