Abstract
Positive response to PD-1/PD-L1 blockades was observed in the treatment of solid tumors. However, the clinical response to PD-1/PD-L1 blockade varied in patients with acute myeloid leukemia (AML). It is thought that there are factors other than PD-1 and PD-L1 that may affect the effect of immunotherapy. This study explored the impact of transcriptome-based co-expression of bromodomain containing 4 (BRD4) and PD-1/PD-L1 on the overall survival (OS) of patients with AML, in order to understand whether BRD4 would affect the effect of PD-1/PD-L1 blockades. Bone marrow samples from 59 AML patients in our clinical center and data of 176 patients from the Cancer Genome Atlas (TCGA) database were used for OS analysis and validation. It was found that increased expression of BRD4 was associated with poor OS in AML patients. Moreover, co-expression of BRD4 with PD-1 or PD-L1 was related to poor OS. The co-expression of BRD4 and PD-L1 was better than BRD4 and PD-1 for OS prediction. Furthermore, co-expression of BRD4 and PD-L1 was positively correlated with high tumor mutation burden, which contributed to poor OS in AML patients. Additionally, the co-expression of BRD4 and PD-L1 was associated with poor OS in non-acute promyelocytic leukemia patients with intermediate/high risk or under 60 years. Our results suggest that transcriptome-based co-expression of BRD4 and PD-L1 is a predictor for poor OS in AML patients, which might provide novel insight into designing combinational targeted therapy for AML.
Highlights
Immune evasion and abnormal immune surveillance of cancers play a crucial role in carcinogenesis and cancer progression (Dunn et al, 2002)
The results showed a clear tendency that high expression of bromodomain containing 4 (BRD4) was related to poor overall survival (OS) in chemotherapy group (p 0.084), while the expression level of BRD4 was not associated with OS in the allo-HSCT group (p 0.217)
Core binding factor acute myeloid leukemia (CBF-AML), nucleophosmin 1 (NPM1) and fms related receptor tyrosine kinase 3 (FLT3) in risk stratification have no impact on the expression of BRD4, PD-1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1) (Supplementary Figures S1A–C)
Summary
Immune evasion and abnormal immune surveillance of cancers play a crucial role in carcinogenesis and cancer progression (Dunn et al, 2002). SD, standard deviation; CBF-AML, core binding factor acute myeloid leukemia; NPM1, nucleophosmin 1; FLT3, fms related receptor tyrosine kinase 3; allo-HSCT, allogeneic hematopoietic stem cell transplantation. PD-L1 expression is closely related to the positive response of PD-1/PD-L1 blockade in solid tumor therapy (Balar et al, 2017; Koemans et al, 2019; Yu et al, 2020). These findings suggest that PD-1/PD-L1 blockade may be a novel immunotherapeutic strategy for AML. It is thought that there are factors other than PD-1 and PD-L1 that may aggravate their immunosuppression, influence their effects on immunotherapy, and contribute to the poor prognosis of AML patients (Stahl et al, 2019; Chen et al, 2020)
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