Dissecting the Immune Landscape of Acute Myeloid Leukemia

Abstract

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

B7-Positive and B7-Negative Acute Myeloid Leukemias Display Distinct T Cell Maturation Profiles, Immune Checkpoint Receptor Expression, and European Leukemia Net Risk Profiles

“…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). Briefly, 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).…”

“…The development of immunotherapy in acute myeloid leukemia (AML) has been hindered so far not only by its remarkable genetic, antigenic, and clonal heterogeneity (10)(11)(12)(13) and the risk of significant off-target hematologic toxicity but also by the lack of biomarkers defining patient populations more likely to benefit from it (9). Recent research revealed that immune profiles are identifiable in human AML and hold prognostic and therapeutic relevance (9,14). The AML immune response shares numerous traits with solid cancers (15) and offers various opportunities for immunotherapy (9).…”

A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

“…For example, CD8+ T cell dysfunction in AML was in part reversible upon PD‐1 blockade in vitro, and PD‐1 blockade could enhance CD33‐CD3 BiTE antibody construct‐mediated cytotoxicity in AML . Thus, it would be interesting to further characterize the complexity of AML‐related T cell immunity, which might support the design of immunotherapies for AML …”

“…14,15 Thus, it would be interesting to further characterize the complexity of AML-related T cell immunity, which might support the design of immunotherapies for AML. 16 Based on TCR composition, T cells are divided in 2 types: TCR + and TCR + T cells. + T cells comprise the majority of T cells (90-95%) in peripheral blood and recognize antigens presented by APC with MHC restriction.…”

Imunophenotypic Evaluation as a Tool for Monitoring Risks for Blood Malignancies in Gas Station Workers

“…The immunophenotyping by flow cytometry is currently one of the fundamental pillars for the diagnosis and classification of lymphoproliferative and myeloid diseases (Craig and Foon, 2009). Immunologic dysregulation can be one cause of these diseases (Davidson-Moncada et al, 2018). The aim of the present study is to apply immunophenotyping as a tool in the biological monitoring of the gas station workers, helping in the diagnosis of benzene poisoning and in the prevention of hematological diseases.…”