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.

MicroRNAs as Modulators of the Immune Response in T-Cell Acute Lymphoblastic Leukemia

“…The interaction of leukemic cells with the microenvironment within the bone marrow niche is a critical step promoting the progression of T-ALL. The triggering of multiple molecular mechanisms shapes immune cell populations involved in the immune surveillance, such as NK cells, various population of T-cells, including regulatory T-cells (Tregs) and MDSCs [ 66 , 67 ].…”

Antibiotics in early life and childhood pre-B-ALL. Reasons to analyze a possible new piece in the puzzle

“…In ALL, pro-inflammatory cytokine signaling including IL6, TNFa and IL-1b is involved in promoting leukemia initiation by cooperating with mesenchymal stromal cell (MSC) niches in selection and induction of ETV6-RUNX1 pre-leukemic cells [ 59 ]. Key cells of the immune system that shape the leukemic microenvironment include immature myeloid populations, non-classical monocytes, macrophages, NK cells, and various subpopulations of T cells [ 60 ]. Immature myeloid populations involved in immunoregulation, referred to as myeloid-derived suppressor cells (MDSCs), include granulocytic (G) and monocytic (M) MSDCs [ 61 , 62 ].…”

Mechanisms of Immunosuppressive Tumor Evasion: Focus on Acute Lymphoblastic Leukemia

“…Immunological evasion is due to mechanisms inherent to the TME. It is well known that malignant blasts maintain a close interaction with normal cells within the BM niche and, at the expense of normal hematopoiesis, remodel functionally and structurally the BM-TME to favor ALL development and promote tumor cell dissemination and chemotherapy resistance (43,47,55,112,118,(182)(183)(184). BM-TME favors tumor growth through polarization of host immunity to prevent anti-cancer immune responses.…”

“…Furthermore, CTLA-4 overexpression has been correlated with the percentage of leukemic B cells and poor prognosis in pediatric patients ( 108 , 110 ), and a high serum CTLA-4 level has been detected in patients with B-ALL who died from the disease ( 111 ). Thus, the disputed CTLA-4 expression from ALL cells could be a potential mechanism of immune surveillance escape ( 109 , 112 ).…”

“…Other cytokines and chemokines, such as IL-1, IL-7, IL-8, CCL2, CXC-10, and CXCL-12, could contribute to immunotolerance ( 112 , 146 ). In fact, IL-1, IL-7, and CXCL12 expression favors ALL cell surveillance in the BM-TME ( 146 , 147 ).…”