High PD-L1 Expression Predicts for Worse Outcome of Leukemia Patients with Concomitant NPM1 and FLT3 Mutations.

Barbora Brodská,Cyril Šálek,Petra Otevřelová,Zdenka Gašová,Ota Fuchs,Kateřina Kuželová

doi:10.3390/ijms20112823

Abstract

Compared to solid tumors, the role of PD-L1 in hematological malignancies is less explored, and the knowledge in this area is mostly limited to lymphomas. However, several studies indicated that PD-L1 is also overexpressed in myeloid malignancies. Successful treatment of the acute myeloid leukemia (AML) is likely associated with elimination of the residual disease by the immune system, and possible involvement of PD-L1 in this process remains to be elucidated. We analyzed PD-L1 expression on AML primary cells by flow cytometry and, in parallel, transcript levels were determined for the transcription variants v1 and v2. The ratio of v1/v2 cDNA correlated with the surface protein amount, and high v1/v2 levels were associated with worse overall survival (p = 0.0045). The prognostic impact of PD-L1 was limited to AML with mutated nucleophosmin and concomitant internal tandem duplications in the FLT3 gene (p less than 0.0001 for this particular AML subgroup).

Highlights

The role of PD-L1 in hematological malignancies is less explored than in solid tumors, and most knowledge is related to the classical Hodgkin’s lymphoma
In the myelodysplastic syndrome (MDS), the chronic myelomonocytic leukemia (CMML), and the acute myeloid leukemia (AML), increased PD-L1 levels were observed on CD34+ cells, whereas stroma/non-blast cellular compartment was positive for PD-1 [11]
We found that a high PD-L1 expression on leukemia blasts predicts for worse overall survival (OS), in patients with internal tandem duplications in Fms-like tyrosine kinase 3 (FLT3) (FLT3-ITD) and with mutated NPM1

Summary

Introduction

The role of PD-L1 in hematological malignancies is less explored than in solid tumors, and most knowledge is related to the classical Hodgkin’s lymphoma (cHL). Frequent PD-1 overexpression on tumor-infiltrating lymphocytes (TILs) enhances the likelihood of successful treatment with checkpoint inhibitors. A PD-1 antibody, has recently been approved for cHL treatment, and additional clinical trials testing the safety and efficacy of other immune checkpoint inhibitors (avelumab, ipilimumab, and pembrolizumab) in cHL are ongoing [3]. The bone marrow microenvironment was shown to induce PD-L1 expression on MM tumor cells [7], and combinatorial checkpoint inhibition, but not the monotherapy, had a therapeutic effect, it was accompanied with severe toxicities [8]. Several studies reported enhanced PD-L1 expression mediating T-cell exhaustion in the chronic lymphocytic leukemia [9,10]. Concurrent induction of the interferon response leads to upregulation of immune checkpoint molecules and to secondary resistance to HMAs [12]. Several other clinical trials combining HMAs with PD-L1 inhibitors are ongoing (see e.g., https://clinicaltrials.gov/)

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Discussion

Conclusion