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.

Fig. 1. AML blast’s immune escaping strategies.

Schematic illustration summarizing the most known immune evasion mechanisms exerted by AML blasts. AML blasts can hamper T- and NK-cell effector functions by aberrantly overexpressing inhibitory T-cell ligands (i.e. PD-L1, Gal-9, CD155, CD112, CD86) (1), or by releasing soluble forms of NKG2DL (2). AML blasts promote T-cell exhaustion and apoptosis, drive the expansion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and induce the switch of macrophages to tumor-associated macrophages (TAMs) (3) by altering the cytokine milieu and through the release within the BM niche of other soluble factors such as reactive oxygen species (ROS), indoleamine 2,3-dioxygenase-1 (IDO1), arginase II (ArgII), and extracellular vesicles (EVs) (4). Moreover, AML blasts reduce their expression of antigen presentation molecules, thus hiding themselves from immune cells such as dendritic cells (DCs) and macrophages (5). Figure created with Biorender.

Fig. 2. Contributions of non-hematopoietic cells in the bone marrow niche to AML immune escape.

Representative mechanisms by which AML-reprogrammed niche cells can promote immune evasion. Mesenchymal stromal cells (MSCs) can regulate the immune response in the leukemic BM microenvironment by secreting a plethora of inhibitory factors, as soluble molecules or as a component of exosomes (1). These factors can inhibit cell proliferation, cytolysis, and production of anti-leukemia cytokines by effector lymphocytes. MSCs mainly through the altered production of CXCL12, interacting with CXCR4, can influence the fate of leukemic cells by triggering their proliferation, spread, and survival and regulate leukocyte migration to the BM niche (2). MSCs and adipocytes regulate the leukemia cells’ metabolism (3). The mitochondrial transfer has recently been appreciated to be a mechanism of intercellular communication associated with chemoresistance and potentially also with immune resistance. Tunneling nanotubules (TNTs) appear to be the primary exchange route used by MSCs to donate mitochondria to AML blasts, boosting oxidative phosphorylation and consequently ROS production which is used by AML blasts as a strategy to evade anti-leukemic effector lymphocytes. A reciprocal relationship occurs between AML blasts and adipocytes wherein malignant cells induce lipolysis from adipocytes and, in turn, adipocytes release fatty acids, which are used as an energy source by malignant hematopoietic cells. Fatty acid oxidation seems to promote the development and activity of immunosuppressive immune cells, such as Tregs and M2 macrophages. The dramatic increase in BM vascular permeability and decrease of blood flow that coincides with leukemic growth can alter the ability of T cells to home, adhere, and extravasate into the leukemic reservoir (4). Figure created with Biorender.