Expression patterns of immune checkpoints in acute myeloid leukemia

Cunte Chen,Yuping Zhang,Shaohua Chen,Yangqiu Li,Chengwu Zeng,Chaofeng Liang,Chi Leong Chio,Shunqing Wang,Caixia Wang

doi:10.1186/s13045-020-00853-x

Abstract

Immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival. This type of therapy is still not available for acute myeloid leukemia (AML). One major issue is the lack of knowledge for the expression patterns of immune checkpoints (IC) in AML. In this study, we first explored the prognostic value of ICs for AML patients by analyzing RNA-seq and mutation data from 176 AML patients from the Cancer Genome Atlas (TCGA) database. We further validated the results of the database analysis by analyzing bone marrow (BM) samples from 62 patients with de novo AML. Both TCGA data and validation results indicated that high expression of PD-1, PD-L1, and PD-L2 was associated with poor overall survival (OS) in AML patients. In addition, increased co-expression of PD-1/CTLA-4 or PD-L2/CTLA-4 correlated with poor OS in AML patients (3-year OS: TGCA data 30% vs 0% and 20% vs 0%, validation group 57% vs 31% and 57% vs 33%, respectively) (P < 0.05). Moreover, co-expression of PD-1/PD-L1, PD-1/PD-L1/PD-L2, and PD-1/LAG-3 was found to correlate with poor OS in AML patients with FLT3mut, RUNX1mut, and TET2mut, respectively. In conclusion, high expression of ICs in the BM leukemia cells of AML patients correlated with poor outcome. The co-expression patterns of PD-1/CTLA-4, PD-L2/CTLA-4, PD-1/PD-L1, PD-1/PD-L1/PD-L2, and PD-1/LAG-3 might be potential immune biomarkers for designing novel AML therapy.

Highlights

Immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival
The black to red or green in the color scale indicates that the range of pixels was from low to high. Kaplan–Meier curves based on the optimal cutoff values. b The overall survival (OS) probability in acute myeloid leukemia (AML) patients with high or low programmed cell death 1 (PD-1), PD-1 ligand 1 (PD-L1), or Programmed cell death ligand 2 (PD-L2) expression in the validation group (n = 62). c Relationship between PD-1, PD-L1, and PD-L2 and other immune checkpoints in the Cancer Genome Atlas (TCGA) group
The red font in the center of the circle displays the Pearson’s coefficient with a P value < 0.05 for the correlation of two immune checkpoints (IC) genes. d, f The OS probability in AML patients with high or low cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and lymphocyte activation gene-3 (LAG-3) based on the optimal cutoff values provided by the X-tile software in TCGA group (d) and in the validation group (f). e The chord diagram shows the co-expression network between PD-1, PD-L1, PD-L2, CTLA-4, and LAG-3 in bone marrow (BM) samples from AML patients in the validation group (n = 62)

Summary

Introduction

Immunotherapy with immune checkpoint inhibitors (ICIs) for solid tumors had significantly improved overall survival. We first explored the prognostic value of ICs in AML patients through analyzing RNA-seq and mutation data from the Cancer Genome Atlas (TCGA) database [6] and further validated the results by quantitative real-time PCR analysis of AML bone marrow (BM) samples from our clinical center. A The OS probability in AML patients with high or low PD-1, PD-L1, or PD-L2 expression in TCGA group.

Results

Conclusion