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Epigenetic Alterations That Are the Backbone of Immune Evasion in T-Cell Malignancies

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10 June 2023

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12 June 2023

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Abstract
Epigenetic alterations are heritable and enduring modifications in gene expression that play a pivotal role in immune evasion. These include alterations to noncoding RNA, DNA methylation, and histone modifications. DNA methylation plays a crucial role in normal cell growth and development but alterations in methylation patterns such as hypermethylation or hypomethylation can enable tumor and viral cells to evade host immune responses. Histone modifications can also inhibit immune responses by promoting the expression of genes involved in suppressing normal immune function. In the case of T-cell lymphoma, adult T-cell Lymphomas (ALT) also undergo immune evasion through the exceptional function of its accessory and regulatory genes. Epigenetic therapies are emerging as a promising adjunct to traditional immunotherapy and chemotherapy regimens. Clinical trials are currently investigating the use of epigenetic therapies in combination with immunotherapies and chemotherapies for more effective treatment of ATL and other cancers. This review highlights epigenetic alterations that are widely found in T cell malignancies.
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Subject: Medicine and Pharmacology  -   Hematology

1. Introduction

Epigenetic alterations are heritable and stable changes in the gene expression that are independent of changes in the underlying DNA sequence [1]. This phenomenon underlies the inheritance of cellular phenotypes and the ability of cells with identical genetic material to differentiate into various types of cells. Epigenetics is an important phenomenon for controlling expression patterns during development, cell cycle, and in response to biological or environmental changes [2]. These alterations mediate environmental effects on gene expression and influence genetic disease risks, providing a valuable tool for understanding how genetic and environmental factors interact to confer disease risk [3]. Environmental factors including pollution, toxicants, inflammation, and nutrients can encourage epigenetic alterations, which in turn can lead to various disorders, including autoimmune disorders, diabetes, and cancers [2,4]. Epigenetic alterations include noncoding RNAs, histone modifications, and DNA methylation.
DNA methylation is an important epigenetic mechanism in mammals, which involves the formation of 5-methylcytosine through the transfer of methyl group onto the cytosine C5 position. The main fundtion of DNA methylation is the regulation of gene expression by employing proteins involved in the repression of genes or through inhibition of transcription factor bindings to the DNA [5]. These modifications play a significant role in sepsis and viral infections. Recent studies have shown that epigenetic alterations have an impact on immune responses [6,7]. The epigenome plays a critical role in the normal development of lymphocytes and the regulation of immune responses [8]. Immune evasion is an approach used by tumors and pathogens to avoid the immune response of the host, promoting their growth and transmission to new hosts [9]. The mechanisms of immune evasion in tumors involve multiple factors that promote antiapoptotic processes, as well as the secretion of immune-suppressive factors in the tumor micro-environment. These factors include transforming growth factor (TGF)-β, interleukin (IL)-10, indoleamine 2,3-dioxygenase, and vascular endothelial growth factor (VEGF), which contribute to the loss of tumor antigen expression and the potentiation of immune-suppressive lymphocytes such as tumor-associated macrophages, regulatory T-cells, and myeloid suppressive cells. Additionally, the expression of inhibitory molecules plays a role in immune evasion [10].
T-cell malignancies are highly malignant and aggressive diseases with poor clinical outcomes. Epigenetic modifications play a critical role in their development and pathogenesis by regulating gene expression and signal transduction [11]. Epigenetic alteration leads to immune evasion in several ways, including changes in DNA methylation patterns. DNA methylation involves the addition of a methyl group to the cytosine base of DNA. Alterations in DNA methylation such as hypomethylation or hypermethylation can lead to immune evasion. Furthermore, the addition or removal of chemical groups to histone proteins can alter their structure and gene expression, leading to changes in immune responses. Histone deacetylation and altered gene expression also contribute to immune evasion [12]. Non-coding RNAs have also been found to play a key role in the alteration of immune responses. Epigenetic changes, inherited across generations can contribute significantly to the alteration of immune responses. The term used for this purpose is transgenerational inheritance [13]. Epigenetic alterations in tumor suppressor genes and oncogenesis contribute towards carcinogenesis. Understanding the genetic and epigenetic components of immune evasion is crucial. Studies on the modulation of epigenetics and immune checkpoints have shown an interaction between immune modulation and epigenetic alterations [14]. This review article provides a comprehensive summary of the latest research on the epigenetic modifications that can result in immune evasion and the development of T-cell malignancies. The article is of great significance as it highlights the emerging importance of epigenetic mechanisms in T-cell malignancies and their potential role in the development of novel therapeutic approaches.

2. Epigenetic Alterations

In the modern era, Human Genome Project is one of the most remarkable accomplishments which sheds light on various surprising mechanisms encoded within the genome. Among these mechanisms, epigenetics has emerged as a crucial factor which represent the chemical interactions and regulatory systems governing genetic code expression. [15]. Currently, regulation of tissue-specific expressions, X chromosome inactivation, or genomic imprinting are the main roles of epigenetic modifications. Additionally, the variability of epigenetic alterations in human disorders particularly cancers has further highlighted the significance of epigenetic regulation mechanisms [16]. Recent breakthroughs in understanding these mechanisms have refined the definition of epigenetics from a process of the development of a fertilized zygote into mature organisms, to an emphasis on the heritability of traits and gene expression mechanisms [17]. Epigenetics is now understood to control both normal and abnormal events in organisms [18]. One of the main activators of epigenetic alterations is environmental stimuli. Chronic inflammation and aging has been identified as activator of aberrant DNA methylation [19,20]. Cigarette smoking is also known to induce invitro abnormal DNA methylation [21]. In the case of cultured epithelial cells of mammals, estrogen treatment is also a well-known abnormal DNA methylation accelerator [22].

3. Epigenetics of Normal Cells

In mammals, epigenetics is an essential mechanism for the development of normal cells and the maintenance of gene expression (tissue-specific) patterns [23]. Chromatin is a set of nucleosomes, that consist of 146 base pairs of wrapped DNA around an octant of 4 core histone proteins. these are H2A, H2B, H3 and H4 [24]. Epigenetics that modify the structure of chromatin can be classified into 4 classes. These categories include DNA methylation, covalent histone modifications, non-covalent mechanisms, and the non-coding RNAs [25].

4. Epigenetics of Abnormal Cells

4.1. Changes in DNA Methylation

The epigenetic profile of cancer cells is different from that of normal cells. There are two types of changes in DNA methylation. Hypomethylation (DNA with less amount of DNA methylation than normal cells) and hypermethylation ( DNA with more amounts of DNA methylation). In cancer cells, across much of the genome, a decreased DNA methylation occurs [27]. This decreased DNA methylation consequences in the alteration of many of the activities of the genes. This is because methylation is linked to low gene activities but in the case of hypomethylation the activity of genes affected is increased [28].
Genes that control cell differentiation and growth typically display less methylation and higher levels of activity, making them prime candidates for the development of cancer [29]. On the other hand, hypermethylation-associated silencing of tumor suppressor genes is a more limited phenomenon that can occur at specific points, or hotspots in the genome. In cancer cells, DNA hypermethylation primarily affects tumor suppressor genes which lead to decreased gene activity and subsequent cancer development [30]. Such hypomethylated and hypermethylated cells tend to develop and grow faster than the normally methylated cells. They grow in abundance and take over the whole population [31]. However, the specific DNA methylation profiles that lead to cancer development can vary greatly between different types of cancer. For instance, while the BRCA1 gene is hypermethylated in ovarian and breast tumors, it is demethylated in other types of tumors [32]. DNA methylation profile in both normal and tumor cells is shown in Figure 1.

5. Immune Evasion Due To DNA Methylation

DNA methylation leads to the silencing of transcription genes, either by recruiting the chromatin-modifying protein or directly inhibiting the transcription factors binding to suppress the gene expression and chromatin structure [34]. Consequently, malignant cells evade detection and attack by natural killer cells and T-cells of the immune system [35]. One of the main immune evasion mechanisms through DNA methylation is the suppression of genes encoding cancer antigens. These antigens are recognized by the immune cells as a foreign agent, after being expressed by the tumor cells [36]. These foreign agents trigger immune responses. However, the silencing or suppression of these antigen-coding genes through DNA methylation renders tumor cells invisible to the immune system, as these genes do not express antigens that can activate the immune system [37].
In a study by Jung et al., they proposed that DNA methylation aberrations play a crucial role in determining how tumors respond to the host immune system. They suggested that such aberrations help highly mutated and rapidly dividing cancer cells to evade the immune system and resist immune therapies. The strategic mechanism involves the heterochromatin formation which is then coupled with an advanced level of methylation loss. This in turn provides support to cancer evolution as they help the cancer cells to evade the immune cells and aid in the fitness of such cells [38]. In another study by Li et al., they reported that the inactivation of histone H3k36, methyltransferase NSD1 induces DNA hypomethylation. This results in reduced immune infiltration of tumor cells. Silencing of genes if innate immunity occurs upon loss of NSD1, these include Type 3 interferon IFNLR1 receptor, through H3K36diemethylation depletion gain of tri methyl H3K27 [39].

6. Downregulation of Antigen Processing

DNA methylation also leads to the deregulation of genes responsible for the presentation and processing of genes. Macrophages and dendritic cells rely on the genes to present and process cancerous antigens to T-cells [5]. On silencing of these genes, cancer cells become resistant to the immune elimination and recognition system. DNA methylation also causes a suppression of chemokines and cytokines expression, which are a necessity of immune cell recruiting to the site of tumor growth or infection [40]. If these signals are not provided to the immune system, it is unable to locate and recognize the tumor cells in the body. This eventually leads to cancer progression and immune evasion [41]. This powerful mechanism of DNA methylation is used by cancer cells to evade the immune destruction and recognition process. It is important to identify and target the immune evasion mediated by DNA methylation, this might help in developing new therapies for cancer and the immune system's power to fight against such cells [42].
Li et al., in 2021, identified that aberrant DNA methylation of PPP2R2B results in tumor suppression in triple-negative breast cancer (TNBC). Analysis was done schematically through bioinformatics. Pieces of evidence obtained through transcriptome, in-vitro experiments, and genome supported that downregulation of PPP2R2B could assist TNBC cells in immune evasion via suppressing the immune response against tumors. Inclusively, PPP2R2B could be a favorable biomarker in the case of TNBC. It also helps in predicting responses to immunotherapies and direct modified TNBC treatment strategies [39].

7. Modification in Histone

Histone methyltransferases (HMTs) carry out the methyl group addition to the histones. The histone demethylase (HDMs) function is opposite to the HMTs. In case of abnormal cell development, methyl groups are placed at the wrong spot when HMT functions are altered, this will lead to the silencing of tumor-suppressing genes[43]. In the same way, HDMS activity is also affected and led to increased oncogenic activity. Histone acetyl markers are lost in the epigenetics of cancer cells because of increased deacetylation of histone [44]. The change of this protein will modify the link between DNA and histones and the shape of complexes of DNA and histones. The methylation effect on the activities of genes varies in according to the amino acid variability. Methyl marks are either regarded as repressing or activating based on their dependence on gene activity. But there is an interesting turnover that few HDMs can eradicate both repressing and activating marks [45].

8. Modification of Histones that Cause Immune Evasion

Immune evasion is also affected by histone modification through an alteration of gene expression involved in immune evasion. These include chemokines, antigen-presenting molecules, and encoding cytokines. Changing the DNA accessibility and transcription binding factors to a certain genetic point. The expression of genes is regulated by the histone modifications in two forms: either suppression of immune-responsive genes or their promotion [46]. Steinbach and Riemer have narrated about the human papillomavirus (HPV) immune evasion mechanism. HPV active immune evasion is mediated intracellularly through disturbed functions of proteins and altered gene expression and interfering extracellularly with immune networks from antigen-presenting cells to T cells. Suppressed IFN and cGAS-STING reaction inhibits the antiviral state induction. Downregulation of adhesion molecules and TLRs plus decreased chemokine production by infected keratinocytes pave the path of reduced antigen-presenting cell attraction and thus consequence in a delayed immune response to Anti-HPV. Interference with antigen processing and low protein expressions add a lot to decreased HPV epitope performance. All these mechanisms help in the persistence of HPV for a long time until it completes its life cycle. But this in turn increases lesion persistence risk and malignant transformation onset [47].

9. Inhibition of Immune Responses

Histone modification can inhibit immune responses by promoting the gene expression involved in inhibiting the immune mechanism [48]. For example, tumor cells can alter histones to overpower the gene expression which encodes the major histocompatibility complex molecules (MHC), which are crucial for presenting the foreign antigen to the T-cells [49]. Histone modification will lead to a suppression of MHC encoding gene expression, so tumor cells will escape recognition from the immune system, and will be avoided by the T-cell destructive mechanism. In addition to this, modification in histones by tumors for the promotion of expression of immune response molecules. For example, PD-L1 inhibits the activation of T cell and hence prevent the immune response [48]. A blockage of T-cell functionality can help lymphomas to evade the recognition and destruction of the immune system [50].

10. Inhibition of Immune Activation

Histone modifications can also evade immune responses by suppressing the immune-activating gene expressions. Such as, in the case o autoimmune disorders, histone modifications can overpower the chemokines and cytokines expressions, which are responsible for promoting immune responses [51]. This will result in a reduction of immune responses and tissue damage will also be reduced, which allows the disorder to persist in the body. Moreover, in case of viral infections, viruses alter histone and this alteration will suppress interferon-stimulated expression which is crucial for the antiviral response of the immune system. Thus viruses evade the immune responses, detection, and destruction by the T-cells [48].
Histone deacetylases (HDACs eliminate the acetyl group from non-histone and histone proteins and play the role of transcriptional repressor. Yeon et al., in 2020 in their study predicted that HDACs are frequently dysregulated in malignancies, regulation of MAPK signaling, progression of cancer cells, and reaction to several anti-tumor drugs. HDACs have been known to regulate the PD-1/PD-L1 expression and genes that contribute towards immune evasion [52]. In short, immune inhibition, and activation-related gene expression can be regulated by histone modifications. Considering the contribution of histone modifications to immune evasion is an important issue and this will contribute a lot to the development of new autoimmune and cancer therapies plus mechanism enhances host and virus interactions [53].

11. Micro RNAs (mRNAs) and Immune Evasion

miRNA are short, endogenous 19-25 nucleotide long, non-coding RNAs that perfectly or partially match the target messenger RNA 3′ untranslated regions (3′UTR) for the regulation of expression of genes through post-transcriptional silencing and degradation of targeted mRNAs [54]. miRNAs have a role in all the processes of life such as cell growth, apoptosis, regulation of cell cycle, stress reaction, and cell differentiation as 30 percent of the human genes are directly targeted by miRNAs, this has been confirmed by the experimental studies and bioinformatics. Sanger miRNA's latest registry annotates that there are more than 800 miRNAs in humans and several more miRNAs are surely be identified in the future[55].
In normal cells, just like other protein-coding genes, miRNAs are tightly regulated for their contributions to the normal cell transcriptome. While in the case of lymphomas, they were found to be very deregulated and massive. The interaction of epigenetic mechanisms and miRNA is a complex regulatory system [56]. There are also pieces of evidence that miRNA is tissue-specific and can affect epigenetic mechanisms such as histone modifications and DNA methylation, and regulate gene transcription and post-transcriptional silencing of genes [56,57].

12. T-Cell malignancies and Epigenetic Alterations

T-cell Lymphoma is a malignancy of T-cells and mature CD+4 cells. This is mainly caused by the T-cell leukemia virus Type 1 (HTLV-1) [58,59]. In comparison with the human immune deficiency virus (HIV) (retrovirus and pathogenic), in vivo HTLV-1 replication level is low, and virions of HTLV-1 transmission are not very efficient [60]. Suppression of infected cell death and clonal proliferation is done by the HTLV-1 for a persistent infection. Immune evasion is also done by this virus through the exceptional function of its accessory and regulatory genes. The survival and proliferation of infected cells lead to the accumulation of epigenetic and genetic aberrations in the genes of the host cells [60].

13. Immune Evasion of T-Lymphoma

Host immunity prevents the development of adult T-cell lymphoma (ATL), due to the immune response towards the HLTV-1. In approximately 90 percent of the ATL cases, immune responses by the host immunity are seen [59]. Strong T-cell responses are recorded in patients who receive a very stressful treatment such as hematopoietic cells[61,62]. Reported results indicated the anti-tumor or anti-viral immune response against the development of T- cell Lymphomas [59]. Despite the immune responses to this viral disease, it has been reported in a recent study that cells of ATL can escape from natural killer cells (NK) mediated immunity through the deregulation of CD48 [63]. This observation suggests that gene silencing for viral expression in cells of ATL and defects in the anti-viral immune responses permits the HTLV-1 infected cells to do immune evasion, survive and transform eventually into clones [59].

14. Epigenetic Regulators of T Lymphocytes

Epigenetic aberrations can lead to transcriptional dysregulations in all types of lymphomas. Epigenetic changes result in the silencing of tumor suppressor genes in their promotor regions. This is an important mechanism in the case of oncogenesis and several other such genes [64]. These include miR-31, p16INK4A, NDRG2, and TCF-8, these greens are well known for their deregulation in the ALT cells by the repressive histone modifications or CpG hypermethylation. [65]. In this way, ALT cells evade the host's immune response and survive [59]. Other main epigenetic regulators of lymphomas include EZH2, KMT2, CREBBP, ARID1A, DNMTA, TET2, and IDH2 [66].

15. Immunotherapy challenges

Identification of biomarkers that envisage clinical responses to PD-1/PDL1 and CTLA-4 blockade is one of the major challenges faced by current immunotherapies[38]. Somatic copy number alterations (SCNAs), genetic alterations of certain types of genes, or in pathways, and tumor heterogeneity have been recognized as the resistance factors of immunotherapies [67,68]. Global methylation also has adverse effects on the checkpoint blockade clinical advantages. On the other hand neoantigen or mutational load and existing T-cell infiltrations are thought to be pointers of the clinical advantage of blockade checkpoints [69]. Chen et al., 2020 hypothesize that treatment with a hypomethylating (HMA) agent would help in the induction of an antitumor immune response to sensitize people suffering from ovarian cancer to the anti-PD-1, immunotherapy. Phase 2 clinical trial was performed by the authors to test the combination of a second-generation HMA, guadecitabine, with an immune PD-1 checkpoint inhibitor, pembrolizumab.
The clinical trial was performed on 35 platinum-resistant patients with ovarian cancer. The hoped result was not attained from the immune checkpoint blockade and HMA but correlation analysis gave information about which immune therapy will be beneficial for people with ovarian cancer [70]. Cellular adoptive therapy, dendritic cell vaccines, and some other strategies have yet to display success for extensive types of tumor cells. As we have talked about above that immune therapy becomes resistant to cancer cells by intrinsic and extrinsic factors in tumor cells that lead to immune evasion. Extrinsic factors are immune suppressive cells such as T regulatory cells, myeloid-derived suppressor cells, and tumor-associated macrophages. These cells secrete and produce immune suppressive aspects and show inhibitory ligands for interaction with receptors of T-cells such as CTLA-4 and PD-1. In this type of therapy, both acquired and primary resistance are a problem. But these PD-1 and CTLA-4 immune checkpoint blockade therapies are known to have some success in immune activation enhancement [35].

16. Prospects of Epigenetic Treatment of Lymphomas

From all the above discussion, it is clear that several studies have shown that epigenetic aberrations are a leading cause of the development and spread of lymphomas. But epigenetic therapies in contrast to chemotherapy which persuades cytotoxicity have a greater effect on cellular processes. For the achievement of a therapeutic effect in the case of lymphomas, reprogramming of cells is done [71]. Epigenetic monotherapy has been known to have auspicious results in recent clinical trials. In this way, many epigenetic agents were approved for use in the lymphoma treatment. Nowadays, immunotherapies and chemotherapies are being used in combination with epigenetic therapies in several clinical trials [72].
This combination therapy is being used to overcome the confrontation with a single agent by cell signaling inhibition bypass pathways and is extensively studied preclinically. Such as BET inhibitors are used in combination with an assemblage of tiny inhibitor molecules including HDACs, EZH2, ATR, BTK, P13K, mTOR plus lenalidomide [73,74].In the same way, decitabine was combined with BET143, AKT, JAK-STAT, and BCL2 inhibitors. Several such combinations are being studied at the preclinical level and some of them are being tried on mice, before their application in humans. The most thrilling avenue for future research studies is the combination of immunotherapy with epigenetic modulating agents [72].

17. Conclusion

Epigenetic alterations are the backbone of several immune evasions mechanism. Alteration in epigenetics leads to several autoimmune disorders diabetes and lymphomas. The normal epigenetic mechanism includes DNA methylation, covalent histone modifications, non-covalent mechanisms, and the non-coding RNAs. Immune evasion results due to alteration in this mechanism: hypomethylation and hypermethylation of DNA suppress the gene expressions that are responsible for detecting the foreign cells and inducing an immune response. Downregulation antigen is also seen in the altered DNA methylation process. Similarly, epigenetic changes in the modifications lead to the suppression or activation of chemokines and cytokines expressions, that alter the actual activity of these genes resulting in the survival and development of tumor cells. T-cell lymphomas are also capable of immune evasion due to antiviral gene suppression in the immune system. Epigenetic therapies are also emerging in addition to the traditional immunotherapy and chemotherapy regimes as a striking add-on. These merging therapies work in synergy with other treatments and offer low toxicity. Further research is required on the novel combinations of inhibiting agents, therapeutic roles, and finding new epigenetic pathways.

Author Contributions

Conceptualization, M.A.; methodology, M.A..; validation, M.A.; formal analysis, M.A..; investigation, M.A..;. resources, M.A.; data curation M.A. ; writing—original draft preparation, M.A.; writing—review and editing M.A.; visualization, M.A.; supervision,M.A..

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. DNA Methylation Backdrop in Normal and Tumor Cells.
Figure 1. DNA Methylation Backdrop in Normal and Tumor Cells.
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