Acute myeloid leukemia (AML) is a molecularly heterogeneous hematological malignancy with variable response to treatment. Recurring cytogenetic abnormalities and molecular lesions identify AML patient subgroups with different survival probabilities; however, 50?70% of AML cases harbor either normal or risk-indeterminate karyotypes.

The discovery of better biomarkers of clinical success and failure is, therefore, necessary to inform tailored therapeutic decisions. Harnessing the immune system against cancer with programmed death-1 (PD-1)-directed immune checkpoint blockade (ICB) and other immunotherapy agents is an effective therapeutic option for several advanced malignancies.

However, durable responses have been observed in only a minority of patients, highlighting the need to gain insights into the molecular features that predict response and to also develop more effective and rational combination therapies that address mechanisms of immune evasion and resistance.

The researchers would review the state of knowledge of the immune landscape of AML and identify the broad opportunity to further explore this incompletely characterized space.

AML-immune interactions

Multiplexed, spatially-resolved immunohistochemistry, flow cytometry/mass cytometry, proteomic and transcriptomic approaches are advancing our understanding of the complexity of AML-immune interactions and are expected to support the design and expedite the delivery of personalized immunotherapy clinical trials.

The research efforts are being devoted to the identification of ICB-responsive TME in patients with solid tumors [100]. Immune gene signatures are an emerging area with great promise for enhancing clinical decision making in patients with hematologic malignancies.

As the field advances our knowledge of immunology, the dynamic and complex nature of patients’ immunological profiles has become increasingly of interest, with factors as diverse as tumor genetics, epigenetics, mRNA expression, micro-RNA expression, patient age, microbiome composition, pharmacological agents and environmental factors, including infections and exposure to sunlight, affecting patient’s immunologic profiles.

Compelling evidence now indicates patients with solid tumors who benefit from ICB typically have an inflamed immune status, with a pre-existing immune response and cytolytic markers with subsequent establishment of immune suppression by various molecular circuits that may be targeted with rational combinations of therapeutics to address distinct mechanism of immune silencing and immune escape (for example IDO1).

Studies in melanoma and other solid tumors have clearly shown that IFN-γ-related mRNA profiles predict clinical response to pembrolizumab. IFN-γ signatures could also identify AML patients with a greater likelihood of responding to immunotherapies, including flotetuzumab, and could reveal novel targets for converting ICB-resistant tumors to a state of responsiveness.

High-dimensional technologies are enhancing our understanding of TME interactions and have the undisputed potential to support the prediction of therapeutic benefit from immune-based interventions.

Because of inherent limitations of gene expression profiles, other approaches, such as flow cytometry, quantitative immunohistochemistry and next-generation sequencing for T cell antigen receptors or similar technologies (multiplex quantitative PCR, spectratyping and immune phenotyping) are recommended to thoroughly characterize the immunological landscape of the TME and to establish predictive models, as recently reviewed by the Immune Biomarkers Task Force of the Society for Immunotherapy of Cancer (SITC).