Acute myeloid leukemia blasts have been shown to differentiate monocytes from healthy donors into an M2-like phenotype in transwell coculture assays indicating that polarization can be achieved by soluble factors alone In the same study, using mouse models of retroviral oncogene-induced AML, greater numbers of macrophages that promote tumor cell line division were found compared with macrophages from control animals While this study showed a potential for M2 macrophages to support tumor growth in mice, it did not measure the effects of macrophages on T cells.
Myeloid-derived suppressor cells are cells of the myeloid lineage associated with chronic inflammation and cancer.
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While there are studies demonstrating a role for MDSCs in suppressing T cell function in AML, there are also studies showing that they may play a lesser role in this disease. It is clear that the potential impact of both macrophage subsets and MDSC on the function of T cells in the AML microenvironment is not fully established and should be a focus of future studies.
Soluble factors, such as enzymes and cytokines, may help tilt the TME from hostile to supportive for tumor cells by suppressing T cell function. In vitro studies suggest the T cell dysfunction seen in AML may be the result of blasts manipulating these soluble factors within the microenvironment 48 , 57 , Orleans-Lindsay et al. These T cells were unable to proliferate in response to mitogenic or alloantigen stimulation but maintained their cytolytic function Interestingly, when the supernatant was removed, there was partial restoration in the T cell response to mitogenic stimulation Mussai et al.
They first showed that arginase II activity is significantly raised in the plasma of patients with AML compared with healthy controls 9. Furthermore, they showed that when T cells were cultured in vitro with the plasma of patients with AML, there was reduced T cell proliferation, which could be relieved via arginine replacement.
In addition to having a directly immunosuppressive effect on T cells, they showed that AML blasts directly polarize monocytes to an M2-like phenotype, further promoting an immunosuppressive microenvironment Indoleamine 2,3-dioxygnenase is an enzyme that catalyzes the oxidation of tryptophan to N -formylkynurenine.
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This enzyme is highly expressed in macrophages and activated dendritic cells. First, elevated systemic levels of kynurenine are detectable in patients with AML and have been shown to negatively correlate with overall survival in patients with intermediate risk disease 62 , IDO-expressing AML cells have been shown to direct the conversion of T effector cells into Tregs and, moreover, this effect can be blocked by the addition of the IDO inhibitor, 1-methyl-tryptophan Mansour et al.
The second signal is a co-stimulatory signal also provided by the APCs. Inhibitory checkpoints are molecules in the immune system that function to fine-tune or turn off an immune response. These molecules initiate intracellular signaling events that interrupt activation cascades, thereby leading to decreased T cell proliferation and cytokine production. This process is critical for the establishment and maintenance of peripheral tolerance during normal immune responses.
Cancer cells can take advantage of this system by expressing the ligands of these checkpoint receptors to turn off the immune system and avoid destruction. Therefore, blocking interactions between checkpoint molecules and ligands might potentially reverse the tumor effect.
The most extensively studied checkpoint molecules are members of the CD28 family, specifically, cytotoxic T-lymphocyte antigen-4 CTLA-4 and programmed cell death protein 1 PD ICIs have received FDA approval for the treatment of melanoma, lung cancer, kidney cancer, head and neck cancer, bladder cancer, colorectal cancer and HL HL is of particular relevance because it is a hematologic malignancy that had previously been shown to overexpress the ligands for PD-1 This established a biological basis for the use of PD-1 blockade therapy in HL and now serves as a model for other hematologic malignancies.
The use of ICIs after allogeneic hematopoietic stem-cell transplant has been explored with promise as ICIs may be expected to increase or reactivate a favorable graft-versus-leukemia response However, this approach has also been taken with great caution, given the possibility of inducing GVHD. While careful consideration is warranted, initial results indicate that administration of CTLA-4 blockade antibody is possible with tolerable side effects in many cases Importantly, clinical responses were observed, including in AML patients.
Clinical trials will continue in the post-allogeneic transplant setting and will yield interesting clinical and mechanistic results [for a concise review of this topic, see Ref. Conversely, CTLA-4 is constitutively expressed on Tregs and provides an activation signal for these cells In addition, Laurent et al. Based on data from treatment of solid tumors, this effect is likely mediated by both enhancement of effector T cell activity and inhibition of Treg function.
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Twelve of the 28 patients treated had AML. Interestingly, four of these patients had extramedullary disease three with leukemia cutis and one with a myeloid sarcoma. In addition, the patients who responded had fewer circulating Tregs in their peripheral blood following initiation of treatment compared with those who did not respond.
These data not only suggest that CTLA-4 blockade may induce a dormant graft-versus-leukemia response but also supports the concept that extramedullary AML may be immunologically distinct compared with AML isolated to the bone marrow and peripheral blood. PD-1 is expressed on the surface of activated T cells. Its ligands, PD-L1 and PD-L2, are expressed on a wide variety of normal immune cells including T cells, monocytes, and dendritic cells. Whether these ligands are constitutively expressed by the leukemia cells or it is an adaptive response to immune pressures, expression by AML blasts has been shown to be associated with a poor prognosis Consistent with this, PD-1 expression has been found to be significantly higher in patients with AML at relapse compared with healthy controls Blockade of PD-1 in this model was shown to result in lower AML burden and longer survival than control mice.
These data implicate PD-1 as a mechanism of immune escape and represent a therapeutic target TIM-3 and its ligand Gal-9 have been identified as a potential target being expressed on AML blasts and leukemic stem cells Although a small study, there appears to be an association with a high percentage of TIM-3 expressing T cells in patients with AML who relapse after allogeneic HSCT compared with those who remain in extended remission, indicating that there is a role for functional T cells in killing AML cells.
Blocking either of these receptors individually was not sufficient to restore function but combined blockade yielded increased tumor rejection and improved survival The accumulation of data to date indicates that TIM-3 will continue to be a promising target on both AML cells and tumor-associated T cells. T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain is a co-inhibitory receptor expressed on activated T cells, Tregs and NK cells.
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When used alone, ICIs may permit the immune system to perform its normal function of tumor clearance. When used in combination, ICIs have the additional potential of enhancing the effect of other therapies, specifically other immunotherapies. Clinical responses to immune checkpoint blockade or vaccines require tumor antigens that can be recognized by T cells.
These antigens can be from various sources, including novel epitopes from non-synonymous coding mutations in genes, developmentally regulated genes with poor tolerance such as Cancer Testis antigens CT antigens or virally associated epitopes. A major class of antigens associated with tumors is derived by DNA mutations. First, the mutation must code an amino acid change non-synonymous mutations.
This mutation must then be expressed at the RNA and protein levels, which would not occur for all mutations detected by DNA sequencing. The new peptides then need to bind MHC molecules in order to be presented to T cells.
Finally, the gene with the mutation must be expressed at sufficient levels by the tumor cells. It is currently believed that antitumor responses from the use of ICIs are related directly to the number of non-synonymous coding mutations present in the tumor. High mutational burden, including those induced by microsatellite instability, has been shown to correlate with response to immune checkpoint blockade — This is not absolute, however, as not all highly mutated tumors respond and some patients with low mutational burden are able to mount a response. This indicates that, while mutational burden is a major factor involved in response to ICI, there are other factors involved.
Recent studies by Schreiber and others have revealed that even when there are hundreds or thousands of DNA mutations in a tumor, only a small number may meet all the abovementioned criteria — Numerous recurrent mutations and drivers associated with AML have been identified , Overall, AML is thought to be of low mutational burden, falling in the lowest quarter of cancer types and therefore may be predicted to respond poorly to ICI therapy There are, however, specific AML subsets that might yield high epitope expression.
These subsets include a p53 loss of function with higher mutational events on average, or a complex karyotype with multiple translocations.
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Another important issue regarding mutations as targets in AML is the diverse clonality of the disease This diversity at the mutational level in a single patient has been associated with resistance to chemotherapy and may present a similar issue for immunotherapies because one clone expressing an immunogenic epitope may not represent the entire tumor. Expression of developmental antigens has long been recognized in AML. These proteins are not expressed or are expressed at low levels in normal adult tissues.
These proteins are often regulated at the level of promoter methylation and are often expressed in cancers due to defects in epigenetic regulation DNA methyltransferase inhibitors, such as azacitidine and decitabine, may increase expression of these antigens and therefore can potentially be used as a method to increase the antigenicity of AML.
The goal of vaccine strategies is to boost the number and activity of tumor-reactive T cells. Vaccines based on tumor-associated antigens have shown immunological responses to the tumor and in the remission setting may result in more prolonged remissions WT1 is a zinc finger containing transcription factor important in the development of the kidney and other organs and is named after its association with Wilms tumor A number of vaccine trials using WT1 peptide vaccines [ and summarized in Ref.
It is important to consider that even if T cells successfully expand through vaccination, they will still face the same suppressive mechanisms as naturally primed T cells. For this reason, strategies combining vaccination with other therapies such as immune checkpoint blockade are more likely to be effective.
The mechanism of action on tumor cells has been assumed to be due to de-methylation and thus increased expression of tumor suppressor genes While these drugs were first appreciated for their ability to suppress leukemia cell counts, recently their effects on the immune system have gained more attention [reviewed in Ref. As described earlier, there has been a substantial body of research showing that hypomethylating agents can increase expression of developmental antigens.
There is also evidence indicating direct consequences of hypomethylating agents on T and NK cells. The indiscriminate nature of their effects on gene promoters results in a complex series of positive and negative effects on T cells. FoxP3 is the lineage-defining transcription factor for Tregs and is regulated at the level of the promoter via methylation. Treatment of T cells with azacitidine results in stable expression of FoxP3 — Furthermore, azacitidine treatment has been shown to suppress T cell proliferation and cytokine production, resulting in suppression of GVHD in mice A similar result was shown in patients following HSCT where treatment with azacitidine was associated with an increase in Tregs While this increase in Treg frequency was observed in patients with MDS being treated with azacitidine, the Tregs isolated from these patients had reduced suppressive capacity Additional mechanisms for hypomethylating agents to promote generalized inflammation include reactivation of endogenous retroviruses that are then recognized resulting in an IFN response.
This response can then synergize with CTLA-4 blockade to induce antitumor immunity , Similarly, expression of costimulatory molecules such as CD80 has been shown to be increased by hypomethylating agents as well, resulting in enhanced antitumor immunity in a mouse model of lymphoma As a result of this information several clinical trials have been initiated to investigate the potential of hypomethylating drugs and immune ICIs for AML Table 1.
Table 1. All of the recent advances in tumor immune therapy come from decades of basic immunology research focusing primarily on autoimmunity. In fact, autoimmunity and tumor immunity represent opposite sides of the same coin, one representing an overactive immune system and the other a suppressed immune system.
By understanding the immunologic mechanisms that lead to disease, we will be better equipped to treat or prevent these diseases. This is highlighted in solid tumors, where immune therapies such as ICI have led to dramatic cure rates in universally fatal diseases. Furthermore, by being able to substitute these therapies for traditional cytotoxic therapies, there is a hope of reducing the acute and chronic toxicities associated with chemotherapy.
With the development of drugs targeting specific signaling pathways and mutations in AML along with epigenetic modifiers there is great potential in the near future to develop strategies that combine the high rates of response of targeted agents with the durability of immune therapies.
Immunotherapies are just now starting to infiltrate the world of AML and the more we learn about the immune microenvironment, the more successful these therapies will become. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. EL receives research funding support in the form of sponsored research projects by the following entities: Janssen Pharmaceuticals, Celgene, and Amgen.
The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer 9 — Graft-versus-leukemia reactions after bone marrow transplantation.
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