Acute Myeloid Leukemia: Is It T Time?

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease driven by impaired differentiation of hematopoietic primitive cells toward myeloid lineages (monocytes, granulocytes, red blood cells, platelets), leading to expansion and accumulation of "stem" and/or "progenitor"-like or differentiated leukemic cells in the bone marrow and blood. AML progression alters the bone marrow microenvironment and inhibits hematopoiesis' proper functioning, causing sustained cytopenia and immunodeficiency. This review describes how the AML microenvironment influences lymphoid lineages, particularly T lymphocytes that originate from the thymus and orchestrate adaptive immune response. We focus on the elderly population, which is mainly affected by this pathology. We discuss how a permissive AML microenvironment can alter and even worsen the thymic function, T cells' peripheral homeostasis, phenotype, and functions. Based on the recent findings on the mechanisms supporting that AML induces quantitative and qualitative changes in T cells, we suggest and summarize current immunotherapeutic strategies and challenges to overcome these anomalies to improve the anti-leukemic immune response and the clinical outcome of patients.

Keywords: T cells; acute myeloid leukemia; immunotherapy; thymus function.

Figure 1

Potential mechanisms leading to thymic atrophy during AML. In the bone marrow (BM), leukemic cells secrete soluble factors that can directly inhibit HSC proliferation and differentiation. They can also produce exosomes that modify the stromal and endothelial cells expression profiles and promote leukemic cells growth and survival. Ultimately, they also compete for spaces and niches of the normal HSC which are required for their survival and proliferation. The alteration in HSC proliferation and differentiation leads to reduced numbers of T-cell progenitors migrating and entering the thymus (ETP) though the blood stream. High concentrations of soluble factors produced by leukemic cells in the blood can also alter the thymic cells (thymocytes and stromal cells) functions and differentiation. HSC: hematopoietic stem cells; CAR: CXCL12-abundant reticular cells; MSC: mesenchymal stem cells; ETP: early T-cell lineage progenitors; BM: bone marrow; PCV: post-capillary venules.

Figure 2

Principal mechanisms leading to peripheral T-cell dysfunctions during AML. In periphery or BM, T cells can present exhausted, anergic and senescent phenotypes with dysregulated functional activities (reduced levels of proliferation, cytotoxicity and cytokines production). Leukemic blasts are mainly responsible for these defects through persistent antigen presentation, inappropriate co-stimulatory signaling and induction of Tregs (ICOSL, PD-L1). Natural Tregs are also recruited abundantly and can participate in these processes. nTreg cell: natural regulatory T cell; iTreg cell: induced regulatory T cell; IL: interleukin.

Figure 3

Promising immunotherapies for the treatment of AML. New immunotherapeutic strategies are under development for the treatment of AML: monoclonal and bi/trispecific antibodies (inhibition of immune checkpoints, targeting of leukemic cells), CAR-T or –allogeneic NK cells against AML blasts surface markers, and improvements in allo-HSCT.