Targeting the Immune Microenvironment in Acute Myeloid Leukemia: A Focus on T Cell Immunity

Abstract

Immunotherapies, such as chimeric antigen receptor T cells, bispecific antibodies, and immune checkpoint inhibitors, have emerged as promising modalities in multiple hematologic malignancies. Despite the excitement surrounding immunotherapy, it is currently not possible to predict which patients will respond. Within solid tumors, the status of the immune microenvironment provides valuable insight regarding potential responses to immune therapies. Much less is known about the immune microenvironment within hematologic malignancies but the characteristics of this environment are likely to serve a similar predictive role. Acute myeloid leukemia (AML) is the most common hematologic malignancy in adults, and only 25% of patients are alive 5 years following their diagnosis. There is evidence that manipulation of the immune microenvironment by leukemia cells may play a role in promoting therapy resistance and disease relapse. In addition, it has long been documented that through modulation of the immune system following allogeneic bone marrow transplant, AML can be cured, even in patients with the highest risk disease. These concepts, along with the poor prognosis associated with this disease, have encouraged many groups to start exploring the utility of novel immune therapies in AML. While the implementation of these therapies into clinical trials for AML has been supported by preclinical rationale, many questions still exist surrounding their efficacy, tolerability, and the overall optimal approach. In this review, we discuss what is known about the immune microenvironment within AML with a specific focus on T cells and checkpoints, along with their implications for immune therapies.

Acute Myeloid Leukaemia in Its Niche: the Bone Marrow Microenvironment in Acute Myeloid Leukaemia

“…T cells are known to be a crucial part of the immune system's defence against malignancy; however, there is increasing evidence to show that T cells can be dysregulated in the presence of AML, and their actions can be subverted to a more immune-suppressed state [44]. Here, the effects on the CD8+ cytotoxic cells and multiple subsets of the CD4 + T cells are considered.…”

“…Here, the effects on the CD8+ cytotoxic cells and multiple subsets of the CD4 + T cells are considered. These mechanisms are important, as T cells have been implicated in the development of treatments for AML, for example creating chimeric T cells specifically targeting the tumour, and that T cells have a role in the success of current treatments such as stem cell transplantation [44][45][46][47]. T cells require co-stimulatory molecules during activation, and this can be counteracted by upregulation of inhibitory molecules, such as programmed cell death (PD-1), CD244, CD160 and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) [44].…”

“…It was also found that expression of TIM-3 and its partner, Gal-9 (expressed on AML cells), was significantly in higher in patients with treatment failure [51]. In contrast, a review by Lamble et al discussed the concept of T cell exhaustion and reduced functionality and reported that there is still contradictory evidence surrounding whether it occurs in AML, perhaps due to the high heterogeneity of the disease [44]. For example, Schnorfeil et al found that while PD-1 was upregulated after relapse, they did not find that this was associated with a functional deficit in the T cells.…”

“…In contrast to the potential reduced function of some T cells in the AML microenvironment, T-regulatory (T-reg) cells are a subclass of T cells which are involved in self-tolerance [44]. They have been found to work in conjunction with AML by creating a localized zone where HSPC can reside on the endosteal surface and improve their survival [58].…”

Harnessing T Cells to Target Pediatric Acute Myeloid Leukemia: CARs, BiTEs, and Beyond

“…In AML, the immune suppressive microenvironment plays an important role in both primary therapeutic resistance and relapse in T cell-based therapies [112]. Immune suppressive cells including regulatory T cells [113,114] and myeloid-derived suppressor cells [115,116] among others can inhibit T-cell function and contribute to exhaustion.…”