Abstract
Acute myeloid leukemia (AML) is generally considered a poorly immunogenic malignancy, displaying a “non-inflamed” leukemia microenvironment (LME), leading to T cell tolerance. However, the immune landscape of AML is much more heterogeneous. Since B7 expression is regarded as a consequence of an interferon-mediated “inflammatory” phenotype, we have investigated by flow cytometry the B7 checkpoint ligands B7.1, B7.2, programmed death ligand 1 (PD-L1), PD-L2, ICOS-L, B7-H3, and B7-H4 on the AML blasts of 30 newly diagnosed patients and their corresponding receptors [cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and inducible T cell costimulator (ICOS)] on bone marrow (BM) T cell maturation populations. We could thus evidence B7-negative and B7-positive leukemias either with an isolated expression or part of eight different checkpoint ligand “signatures” that always included an inhibitory B7 molecule. B7-positive AMLs encompassed intermediate and adverse European Leukemia Net (ELN) risk cases and displayed mainly central memory CD4+ T cells with high ICOS levels and effector CD8+ T cells with high PD-1 expression. B7-negative cases were rather classified as AML with recurrent genetic anomalies and displayed predominantly naive T cells, with the exception of NPM1 mutated AMLs, which expressed B7-H3. These different B7 immune profiles suggest that specific immunotherapies are required to target the distinct immune evasion strategies of this genetically heterogeneous disease.
Highlights
The last decade has witnessed dramatic advances in the field of cancer immunotherapy
Well-beyond investigating the expression of isolated molecules, our study aims to simultaneously evaluate the B7 checkpoint ligand phenotype of Acute myeloid leukemia (AML) blasts (B7.1, B7.2, programmed death ligand 1 (PD-L1), PD-L2, ICOS-L, B7-H3, B7-H4) and the expression of immune checkpoint receptors (ICRs) [inducible T cell costimulator (ICOS), programmed death 1 (PD-1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4)] on helper and cytotoxic T cell maturation populations and to correlate these data to standard prognostic factors
AML diagnosis was established according to the WHO diagnostic criteria [34], and patients were risk-stratified in accordance with the 2017 European Leukemia Net (ELN) recommendations [35]
Summary
The last decade has witnessed dramatic advances in the field of cancer immunotherapy. Immune checkpoint blockade (ICB) is reshaping the treatment paradigm of solid tumors [1] and hematologic cancers, such as Hodgkin lymphoma [2]. Gene expression profiling (GEP) of tumor immune microenvironments is revolutionizing our understanding of cancer-immune interactions. Several recurrent pan-cancer immune profiles have been identified and could serve as biomarkers for predicting clinical responses to immunotherapy or for tailoring personalized treatment strategies [7, 8]. Tumors with inflamed type I and II interferon (IFN)-driven immune microenvironments (informally designated as “hot”) are ICB responsive, while “cold” “immune-desert” tumors would rather benefit from adoptive cell transfer or tumor–peptide vaccination [9]
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