The Interplay Between the Genetic and Immune Landscapes of AML: Mechanisms and Implications for Risk Stratification and Therapy

Abstract

AML holds a unique place in the history of immunotherapy by virtue of being among the first malignancies in which durable remissions were achieved with “adoptive immunotherapy,” now known as allogeneic stem cell transplantation. The successful deployment of unselected adoptive cell therapy established AML as a disease responsive to immunomodulation. Classification systems for AML have been refined and expanded over the years in an effort to capture the variability of this heterogeneous disease and risk-stratify patients. Current systems increasingly incorporate information about cytogenetic alterations and genetic mutations. The advent of next generation sequencing technology has enabled the comprehensive identification of recurrent genetic mutations, many with predictive power. Recurrent genetic mutations found in AML have been intensely studied from a cell intrinsic perspective leading to the genesis of multiple, recently approved targeted therapies including IDH1/2-mutant inhibitors and FLT3-ITD/-TKD inhibitors. However, there is a paucity of data on the effects of these targeted agents on the leukemia microenvironment, including the immune system. Recently, the phenomenal success of checkpoint inhibitors and CAR-T cells has re-ignited interest in understanding the mechanisms leading to immune dysregulation and suppression in leukemia, with the objective of harnessing the power of the immune system via novel immunotherapeutics. A paradigm has emerged that places crosstalk with the immune system at the crux of any effective therapy. Ongoing research will reveal how AML genetics inform the composition of the immune microenvironment paving the way for personalized immunotherapy.

Acute Myeloid Leukemia: From Biology to Clinical Practices Through Development and Pre-Clinical Therapeutics

“…Indeed TIM-3 is involved in an autocrine stimulatory loop in AML LSCs. Besides, MDSC and M2-polarized macrophages are associated with a poor prognosis, in a manner similar to that of high proportions of M1-polarized macrophages (57,65). Fatty acid and lipid mediators also modulate the leukemia microenvironment via immune signaling (71).…”

“…Additionally, certain processes that indicate immune dysregulation and leukemia microenvironment remodeling have been described in AML as follows: low neoantigen burden and defective antigen presentation; higher regulatory/suppressive T-cells (Treg) proportion and lower T effector (Teff) proportion; T-cells exhaustion due to upregulation of immune checkpoint ligands and receptors; chronic inflammation and increase of inflammatory macrophage population (M1); increase of myeloid derived suppressor cell population (MDSC) and suppressive macrophage population (M2) derived from both normal progenitors and leukemia cells; and production of immunosuppressive soluble factors and metabolites ( 64 , 65 ). Antigen presentation by MHC class II genes is reportedly downregulated during relapse following allogeneic stem cell transplantation (ASCT) ( 66 ).…”

“…Indeed, AML is considered to present a low mutational burden and thereby low immunogenicity. Nevertheless TP53-mutated AML should be associated with an increased mutation burden and efficacy of ASCT, indicating sufficient immunogenicity ( 65 ). In addition, bone marrow T-cells overexpress PD1 and CTLA-4 while LAG-3 and T-cell Immunoglobulin Mucin-3 (TIM-3) are not overexpressed ( 57 , 65 , 68 ).…”

“…Nevertheless TP53-mutated AML should be associated with an increased mutation burden and efficacy of ASCT, indicating sufficient immunogenicity ( 65 ). In addition, bone marrow T-cells overexpress PD1 and CTLA-4 while LAG-3 and T-cell Immunoglobulin Mucin-3 (TIM-3) are not overexpressed ( 57 , 65 , 68 ). Type I and II interferons also induce the expression of PD-L1/2 in AML blasts ( 69 , 70 ).…”

Immunotherapy in Hematologic Malignancies: Emerging Therapies and Novel Approaches

“…Despite extensive studies and the well-defined mechanism of AML, treatment methods have not changed much in the past 30 years, and, more importantly, AML is successfully cured in only 35-40% of patients <60 years of age and 5-15% of patients >60 years of age [60]. Of note, AML was the first malignancy in which durable remissions were achieved by allogeneic hematopoietic stem cell transplantation (HSCT), the most potent antileukemic, and an immunotherapeutic approach [61]. It is believed that its curative effect is based on the graft-versus-leukemia effect of allogeneic T cells on AML cells.…”