As CTLA-4 and CD28 share CD80 and CD86 as their common ligands, resulting in either T cell inhibition or stimulation, investigators have explored the expression of CD80 and CD86 by leukemic cells

As CTLA-4 and CD28 share CD80 and CD86 as their common ligands, resulting in either T cell inhibition or stimulation, investigators have explored the expression of CD80 and CD86 by leukemic cells. in acute leukemia, which seek to harness the bodys own immune system to fight leukemic cells. Keywords: Acute lymphoblastic leukemia, acute myeloid leukemia, co-inhibitory receptor, immune checkpoint pathway, immune evasion, immunotherapy, monoclonal antibody, T cells 1. INTRODUCTION The functionality of T cells during immunity and tolerance is determined by the balance between co-stimulatory and co-inhibitory signals that fine-tune the amplitude, quality, and duration of T cell responses that are initiated upon antigen recognition by T cell receptors (TCRs) [1C3]. While engagement of a co-stimulatory receptor such as CD28 strongly amplifies antigen-specific TCR signaling with a resultant increase in lymphocyte proliferation and activation, co-inhibitory receptors serve as immune checkpoints to prevent and limit uncontrolled T cell responses. In healthy individuals, immune checkpoints are crucial for maintaining self-tolerance, and thus preventing autoimmunity, and for limiting tissue damage when the immune system responds to infection. Tumor cells, however, can hijack these inhibitory pathways to evade immune recognition and consequent destruction by tumor antigen-specific cytotoxic T lymphocytes (CTLs; also known as CD8+ effector T cells). Under normal physiological conditions, the adaptive immune system is highly capable of recognizing and killing foreign cells, including aberrant tumor cells. However, differential expression of co-stimulatory and/or co-inhibitory molecules, among other immune escape mechanisms coopted by tumor cells, can dominantly diminish tumor-specific T cell responses [4, 5]. Sustained signaling via co-inhibitory molecules results in functional exhaustion of T cells, during which their ability to proliferate, secrete cytokines, and mediate lysis of tumor cells is sequentially lost [6]. Thus, these mechanisms ultimately contribute to immune escape by cancer cells [4, 7C9]. In this review, we will address the role of co-inhibitory molecules in immune evasion in acute leukemias and discuss the impact of blocking co-inhibitory molecule signaling in order to circumvent T cell inhibition. 2. Bifenazate ANTI-LEUKEMIC IMMUNE RESPONSES The most convincing evidence that an intact immune system is highly potent in Bifenazate eliminating leukemia cells is seen in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) [10]. The anti-leukemic effect of allo-HSCT depends on the ability of immunocompetent donor T cells to recognize major histocompatibility antigens (MHAs) and/or minor Bifenazate histocompatibility antigens (MiHAs) present on residual leukemia cells and eliminate them, mediating the so-called graft-versus-leukemia Bifenazate (GVL) effect [11]. The best demonstration for the T cell-mediated GVL effect has been provided by the efficacy of donor lymphocyte infusion (DLI) in inducing disease remission in patients relapsing after allo-HSCT [12]. Besides this allogeneic anti-leukemic effect, there is also evidence for autologous anti-leukemic reactivity. Leukemia-specific cytolytic activity has been reported in patients after autologous HSCT [13], and T cell lines capable of lysing autologous acute myeloid leukemia (AML) cells have been generated [14]. Moreover, simple co-culture of monocyte-derived dendritic cells (DCs) with leukemic blasts, both derived from the peripheral blood (PB) of patients with Itgb2 AML, effectively activated leukemia-specific autologous T cells [15]. Nonetheless, leukemia cells exploit a variety of mechanisms to evade T cell-mediated immunity, leading to disease progression or relapse. 3. DYSREGULATION OF THE IMMUNE SYSTEM IN ACUTE LEUKEMIA With the exception of immune checkpoint pathways, which will be discussed separately below, several innate and adaptive immune system aberrations encountered in patients with acute leukemia are summarized in Table 1. However, in any given leukemia patient, multiple mechanisms likely cooperate to create an environment that supports the immune escape of leukemia cells. Table 1 Immunologic Changes in Patients with Acute Leukemia*. [186]36 absolute number of CD8+ T cells. numbers of CD3+CD56+ NK-T cells.Aberrant T cell activation pattern.Impaired immune synapse formation between T cells and AML blasts.Newly diagnosed AMLPBKanakry [25]20Tregs represent an expanded T cell population in early lymphocyte recovery after intensive induction chemotherapy.Tregs are oligoclonally skewed and primarily peripherally derived. Newly diagnosed AMLPBShenghui [26]182 Tregs compared.