Identification of phenotypic profiles in children and adult patients with AML using immune gene expression profiling – AML Global Portal coverage at 2018 ASCO-SITC

At the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, San Francisco, CA, USA, Sergio Rutella, from the John van Geest Cancer Research Centre, Nottingham Trent University, UK, and colleagues presented data from their study, which aimed to identify comprehensive immune profiles across the biological heterogeneity of pediatric and adult Acute Myeloid Leukemia (AML), with the aim to implement new molecularly targeted agents for patients with specific immunologic profiles of AML. 

Bone Marrow (BM) samples at diagnosis from pediatric (n = 39, median age at diagnosis = 10 years) and adult (n = 28, median age at diagnosis = 55.5 years) patients with AML were collected and analyzed in this study. A total of 90 samples from de novo AML (n = 63), AML in CR (n = 18) and relapsed AML (n = 9) were analyzed on the nCounter® System (a fully automated digital platform for gene expression analysis) using the RNA Pan-Cancer Immune Profiling Panel (detects the expression of genes for 109 cell surface markers on 24 immune cell types, and > 500 immune response genes).

Key findings:

• Differences in immune gene expression levels were observed between pediatric and adult patients with AML
  • Genes highly expressed in adult AMLs compared with childhood disease included chemokine, dendritic cell, and macrophage genes
  • Genes down-regulated in adult compared with childhood AMLs included integrin family members, cytokine receptors, T-cell receptor complex components (CD3EAP) and lipocalin-2 (LCN2)
• Hierarchical clustering on BM samples identified subgroups including immune-enriched and immune-depleted AMLs
  • Immune-enriched AMLs had increased expression of lymphocyte –associated genes (NK cell and cytotoxicity genes), immune checkpoints (LAG3, CTLA4 and PDL1), chemoattractant (CXCL10, CXCL9) and inhibitory molecules (indoleamine 2,3-dioxygenase-1 [IDO])
  • Immune-enriched AMLs had an increased expression of CD8A, IFNG, FOXP3
  • Immune-depleted AMLs over-expressed genes involved in mast cell functions and CD8 T- cell exhaustion
  • Immune-depleted samples associated with low expression of T-cell and B-cell genes

The authors then investigated the correlation of the transcriptomic and proteomic profiles with patient outcome. 

• Survival in patients with immune-enriched and immune-depleted AML respectively were:
  • Relapse-free survival: 2.2 vs 18.3 months, HR = 2.48, P = 0.0064
  • Overall survival: 6.3 vs 22.4 months, HR = 2.39, P = 0.017

In order to identify leukemia-immune system interaction, Digital Spatial Profiling (DSP) was used to visualize 10 BM biopsies from patients with newly diagnosed AML. It was observed that there was co-localization of CD8 T cells with FoxP3 Treg cells and PD-L1- and VISTA-expressing cell types thus suggesting “an immune landscape which is consistent with the establishment of adaptive immune resistance mechanisms of immune escape”.

The speaker, Sergio Rutella, concluded by stating that their study identified distinct immune gene profiles among children and adults with AML. They further added that immune gene expression profiles might support the rapid prediction of relapse, identify novel immune biomarkers and therapeutic targets and can be used for the development of an integrated patient stratification.

Additionally, the speaker noted that patients with immune enriched AMLs had shorter RFS and OS and thus suggested that “immune enriched AMLs might be amenable to immunotherapy approaches tailored to the BM microenvironment including blockade of co-inhibitory molecules and/or small-molecule IDO1 inhibitors.”