Catch me if you can: how AML and its niche escape immunotherapy

Abstract

In spite of the remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML), the five-year survival rate of AML patients remains poor, highlighting the urgent need for novel and synergistic therapies. Over the past decade, increased attention has been focused on identifying suitable immunotherapeutic strategies for AML, and in particular on targeting leukemic cells and their progenitors. However, recent studies have also underlined the important contribution of the leukemic microenvironment in facilitating tumor escape mechanisms leading to disease recurrence. Here, we describe the immunological features of the AML niche, with particular attention to the crosstalk between the AML blasts and the cellular components of the altered tumor microenvironment (TME) and the mechanisms of immune escape that hamper the therapeutic effects of the most advanced treatments. Considering the AML complexity, immunotherapy approaches may benefit from a rational combination of complementary strategies aimed at preventing escape mechanisms without increasing toxicity.

Scalable Enrichment of Immunomodulatory Human Acute Myeloid Leukemia Cell Line-Derived Extracellular Vesicles

“…The scalable workflow for AML-EV isolation established in this study may, thus, serve as a technology supporting further research toward therapeutic targeting of the deleterious immune escape effects of AML-EVs. Our observation that AML-EVs but not the AML cells or their secreted soluble factors also inhibit T cell proliferation might relate to the higher level of complexity of the immunosuppressive functions of AML-EVs [ 66 ]. Both T cell- and NK cell-based functional assays may serve as screening readouts to identify druggable targets.…”

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

“…T cells express the respective co-inhibitory receptors (IRs), including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain 3 (TIM-3), lymphocyte activating-3 (LAG-3), and T cell immuno-receptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) [ 128 ]. At the same time, AML cells overexpress the regulatory ligands, such as programmed death-ligand 1 (PD-L1), B7-H3 (CD276), and Galectin 9 (Gal-9), CD112, CD155 ( Figure 2 A) [ 129 , 130 ]. These mechanisms of AML immune evasion are recognized as fundamental for the relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT).…”

“…A comprehensive discussion of all these mechanisms is out of the scope of the present review [ 128 , 130 ]. Below we will focus on Tregs and Teffs.…”

Innate Immune Mechanisms and Immunotherapy of Myeloid Malignancies

“…In AML, there are many mechanisms of immune evasion and suppression by the leukemia cells. These may include secretion of cytokines and other factors that alter the bone marrow niche, upregulation of inhibitory T-cell ligands, and expansion of regulatory T cells and myeloid-derived suppressor cells [ 67 ]. A recent study on IFN-α treatment for minimal residual disease (MRD) positive t(8;21) AML patients after allo-HSCT reported a 2-year OS of 92.3%, compared to 51.4% in historical cohorts [ 68 ].…”