Mechanisms of Immune Evasion in Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) results from a clonal expansion of abnormal lymphoid progenitors of B cell (BCP-ALL) or T cell (T-ALL) origin that invade bone marrow, peripheral blood, and extramedullary sites. Leukemic cells, apart from their oncogene-driven ability to proliferate and avoid differentiation, also change the phenotype and function of innate and adaptive immune cells, leading to escape from the immune surveillance. In this review, we provide an overview of the genetic heterogeneity and treatment of BCP- and T-ALL. We outline the interactions of leukemic cells in the bone marrow microenvironment, mainly with mesenchymal stem cells and immune cells. We describe the mechanisms by which ALL cells escape from immune recognition and elimination by the immune system. We focus on the alterations in ALL cells, such as overexpression of ligands for various inhibitory receptors, including anti-phagocytic receptors on macrophages, NK cell inhibitory receptors, as well as T cell immune checkpoints. In addition, we describe how developing leukemia shapes the bone marrow microenvironment and alters the function of immune cells. Finally, we emphasize that an immunosuppressive microenvironment can reduce the efficacy of chemo- and immunotherapy and provide examples of preclinical studies showing strategies for improving ALL treatment by targeting these immunosuppressive interactions.

Keywords: B cell; NK cell; T cell; acute lymphoblastic leukemia; bone marrow; immune evasion; immune system; immunotherapy; macrophage; microenvironment.

Figure 1

Leukemic microenvironment supports survival of acute lymphoblastic leukemia (ALL) cells and their immune evasion through multiple interactions. Various cell populations shape the leukemic microenvironment. Regulatory T cells (Tregs) secrete inhibitory cytokines that suppress the cytotoxic activity of T cells and reduce macrophage phagocytosis. Granulocytic Monocyte Derived Suppressor Cells (G-MDSC) produce reactive oxygen species (ROS) that inhibit activity of T cells and natural killer (NK) cells. NK cells express low levels of natural cytotoxicity triggering receptor p46 (NKp46) activating receptor, while ALL cells downregulate major histocompatibility complex class I-related chains A/B (MIC-A/B)-a ligand for natural killer group 2 member D (NKG2D) activating receptor. ALL also drives NK cell dysfunction by secreting immunosuppressive transforming growth factor beta (TGF-β). Mesenchymal stem cells (MSCs) secrete chemokines, e.g., C-X-C chemokine ligand 12 (CXCL12), which binds C-X-C chemokine receptor type 4 (CXCR4) and promotes ALL engraftment into the vascular niche. Furthermore, MSCs protect ALL cells against the treatment by secretion of galectin-3, which activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. MSCs also secrete metabolites, such as asparagine, which reduces the cytotoxicity of L-asparaginase. Non-classical (CD16⁺) monocytes infiltrate the leukemic microenvironment and are thought to be involved in ALL cells protection. Macrophages from the leukemic niche acquire immunosuppressive properties and secrete tumor-promoting cytokine TGF-β. Their phagocytic activity is reduced by the interaction of signal regulatory protein α (SIRPα) with cluster of differentiation 47 (CD47)—a “do not eat me signal” expressed by leukemic cells. The figure was created in BioRender (https://biorender.com/; accessed on 27 February 2021). Other abbreviations: CD200, cluster of differentiation 200; CD200R, CD 200 receptor; G-MDSC, Granulocytic Monocyte Derived Suppressor Cells; IL-10, Interleukin 10; TIM3, T-cell immunoglobulin domain and mucin domain 3.