What is Epigenetic regulation in tumor immunity?
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What is Epigenetic regulation in tumor immunity?
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What is Epigenetic regulation in tumor immunity?
Both genetic and epigenetic changes are important factors in carcinogenesis, tumor progression and metastasis. Broadly speaking, the incidence of cancer is directly related to biological/genetic age. DNA methylation is an important epigenetic regulatory mechanism that changes continuously during the life cycle and is an important part of the process of “epigenetic aging”. Notably, recent studies have demonstrated that epigenetic senescence plays a major role in tumorigenesis.
Epigenetic alterations contribute to cancer development by affecting multiple oncogene and tumor suppressor gene pathways in a wide range of histologies, as well as by affecting the activation, differentiation and function of immune cells such as T cells and NK cells . In fact, a recent study has shown that it is tissue environment-induced epigenetic programming that initiates tumorigenesis, findings that provide a strong rationale for the application of epigenetic medicines not only as cancer therapeutics, but also Can be used to prevent cancer because they can synergistically target “normal” cells, including immune cells and precancerous cells.
Epigenetics-based therapies aim to modulate transcriptional programming that affects various signaling pathways in immune cells, other normal cells, and/or cancer cells, thereby affecting the fate of these cell populations. Epigenetic drugs are chemicals that act on a cell’s epigenome to perform its functions, these drugs include DNA methyltransferases ( DNMTs ), DNA demethylases, histone deacetylases ( HDACs ), histone acetylases Inhibitors of transferases ( HATs ), histone methyltransferases ( HMT ), histone demethylases ( HDMs ) and other related enzymes. In addition, microRNAs ( miRNAs ) and long noncoding RNAs ( lncRNAs ) are also important epigenetic mediators of multiple key biological processes, including carcinogenesis and immune responses, two key targets for effective cancer therapy.
As a major epigenetic mark, DNA methylation is inherited through mitosis and is involved in stable gene transcriptional repression, especially when it is located near the transcriptional start of mammalian genes. The most intensively studied covalent modification of DNA is 5-methylcytosine ( 5mC ), a label catalyzed by DNMT.
In mammalian genomes, 5mC is mainly present in CpG dinucleotides, and 70–80% of the 28 million CpG dinucleotides in the human genome are methylated. In mammals, three active DNMTs have been identified, named DNMT1, DNMT3a, and DNMT3b.
Histones can undergo various forms of post-translational modifications ( PTMs ), including acetylation, methylation, phosphorylation, ubiquitination, as well as ADP ribosylation, sulfonylation, and citrullination. These make up the so-called “histone code” that regulates chromatin structure, recruitment of remodeling enzymes and regulation of gene activity.
Acetylation of histone lysine residues affects genome organization and function. Acetylation of histones H3 and H4 is determined by two groups of enzymes: HATs and group HDACs. These two groups of enzymes determine the acetylation state of histones and work in a reversible manner.
In humans, there are 18 HDAC enzymes divided into four classes: class I of Rpd3-like proteins ( HDAC1, HDAC2, HDAC3, and HDAC8 ); class II of Hda1-like proteins ( HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10 ) ; Class III ( SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, and SIRT7 ) and class IV proteins ( HDAC11 ) of Sir2-like proteins. These enzymes and their functions in cancer have been extensively studied.
Histone methylation is the third major type of epigenetic modification. To accomplish this reversible process, two broad classes of enzymes that catalyze methyl addition are involved: protein arginine methyltransferases ( PRMTs ) and histone lysine methyltransferases ( HKMTs ). Key lysine and arginine methyltransferases in the cancer environment include zeste homolog 2 ( EZH2 ), G9a, DOT1L, and PRMTs 1 and 5. Another group of enzymes called histone demethylases reverse this process.
Phosphorylation is another highly dynamic form of histone PTMs. It occurs on serine, threonine and tyrosine residues, mainly in the N-terminal tail of histones, and is controlled by the competitive action of kinases and phosphatases. As an important part of the “histone code”, PTMs play key roles in DNA damage repair, chromatin compaction, transcriptional regulation, and a range of biological processes including tumorigenesis and cancer progression.
Epigenetic regulation of the tumor microenvironment
The tumor microenvironment ( TME ) consists of multiple cell types. In addition to tumor cells, the TME contains a variety of non-epithelial cell types, including cells that make up the vasculature ( endothelial cells, pericytes, and smooth muscle cells ), cells involved in immune surveillance ( lymphocytes, macrophages, and mast cells ), and stroma cells (i.e. , fibroblasts ) that secrete a range of diffusible growth factors, cytokines, and chemokines in the extracellular matrix ( ECM ). It has long been recognized that carcinogenesis promotes stromal changes characterized by pro-angiogenic growth factor expression, altered ECM expression, accelerated fibroblast proliferation, and increased inflammatory cell infiltration.
Epigenetic alterations in the TME control tissue hypoxia and play critical roles in cellular responses to hypoxia and cancer cell metabolism. Epigenetic regulators can work in concert with the hypoxia-inducible transcription factor ( HIF ) family of genes to maintain a hypoxia-adapted cellular phenotype long after HIF-dependent initiation. Epigenetic changes stabilize the binding of HIF to its transcriptional targets, thereby affecting histone demethylase activity following direct HIF transactivation, and ultimately leading to the overall pattern of histone modifications and DNA methylation in the hypoxic TME, Hypoxic upregulation of JMJD1A expression acts as a signal amplifier to promote hypoxic gene expression, ultimately promoting tumor growth.
Macrophages are key innate immune cells in the TME, where they regulate primary tumor growth, angiogenesis, metastatic spread, and tumor response to interventional therapy. In macrophages, hypoxia attenuated the expression of Jumonji histone demethylase activity, resulting in increased histone H3K9 methylation and decreased chemokine expression, resulting in changes in the immune landscape within the TME.
Epigenetic regulation of immune cells
Epigenetic mechanisms play critical roles in immune cell differentiation and function, ensuring appropriate gene expression patterns in immune cells under different tissue microenvironmental conditions. Importantly, epigenetic mechanisms play a decisive role in immune and stromal cell types within the TME.
Innate immune cells (myeloid cells and NK cells)
Myeloid cells play an important role in the recognition of cancer cells by the adaptive immune system and coordinate the initiation of inflammatory and protective antitumor immune responses. These cells include granulocytes, monocytes, macrophages, neutrophils, DCs and MDSCs.
DC cells initiate and coordinate adaptive immune responses against infection and disease, and they are central to the development of immune memory and immune tolerance. Dendritic cells rapidly integrate signals from their tissue microenvironment and respond to those signals accordingly, and this dynamic change relies on epigenetic changes in the chromatin structure of DC cells.
In macrophages, their functionally polarized state requires precise temporal and contextual regulation of target gene expression. Epigenetic changes play a role in altering cellular signaling and signature gene profiles during M1 and M2 polarization.
MDSCs are induced during tumorigenesis, and they mediate potent tumor-promoting activities. Studies have shown that in the presence of tumor-associated media, there are extensive demethylation and DNA methylation at some specific sites in the genome of MDSCs, which are associated with increased immunosuppressive signature-specific genes.
Furthermore, numerous studies have shown that epigenetic pathways of histone modifications regulate various aspects of MDSCs. For example, HDAC11 is a novel epigenetic regulator that regulates cell expansion and function in tumor-associated MDSCs.
NK cells play an important role in immune surveillance and elimination of stressed, infected or transformed cells. For NK cells, the H3K4me3 demethylase Kdm5a is required for cell activation.
Furthermore, chronically stimulated NK cells exhibit dysfunction when reactivated by tumor targets, and these anergic NK cells exhibit specific epigenetic reprogramming patterns with genome-wide alterations in DNA methylation.
CD4+ T cells
Epigenetic mechanisms play key roles in the cellular differentiation and function of Th1 and Th2 cells. STAT4 and STAT6 transcription factors play regulatory roles in epigenetic modification and transcriptional regulation during helper T cell differentiation.
The study found that STAT4 has a more pronounced role in promoting active epigenetic marks, while STAT6 has a more pronounced role in antagonizing repressive markers.
For T follicular helper ( Tfh ) cells, it has been demonstrated that the VHL-HIF-1α axis plays an important role in initiating Tfh cell development through epigenetic reprogramming of glycolysis.
EZH2 is an HMT that catalyzes H3K27me3 and affects Th1, Th2 and Treg cells primarily through HMT activity. Studies have shown that EZH2 knockdown impairs Tfh differentiation and activation of transcriptional programming.
The development of Treg cells is critically dependent on FoxP3, and FoxP3 expression is required for optimal Treg repressive activity, and studies over the past few decades have shown that DNA methylation of CpG islands in enhancer regions controls FoxP3 expression in T cells.
In addition, TET-methylcytosine dioxygenase is also critical for the functional stability of Treg cells. A series of studies have demonstrated the critical role of TET in maintaining stable FoxP3 expression in Treg cells.
The importance of EZH2 in Treg cells was also confirmed. EZH2 is critical for both Treg differentiation and T effector cell expansion, disrupting EZH2 activity in Treg cells by genetic or pharmacological means leads to tumor-infiltrating Treg cells acquiring pro-inflammatory functions, remodeling the TME, and enhancing CD8+ and CD4+ effectors Recruitment and function of T cells, thereby eliminating tumors.
CD8+ T cells
Epigenetic regulation of gene expression plays a key role in acquiring and maintaining the effector functions of CD8+ T cells, as well as the rapid and robust response of memory CD8+ T cells to antigenic rechallenge. Epigenetic mechanisms also influence the stemness and fate of CD8+ T cells.
Histone acetylation promotes rapid and robust memory responses in CD8+ T cells through differential expression of effector molecules. The effector gene H3 lysine 9 acetylation ( H3K9Ac ) was significantly increased in memory CD8+ T cells compared to naive CD8+ T cells. Furthermore, HDAC3 has been identified as an epigenetic regulator of CD8+ T cell effector differentiation and cytotoxic potential.
Epigenetic regulation of tumor cells and immune molecules
Metabolic reprogramming of cancer cells, a well-recognized hallmark of cancer, has emerged as a key immunosuppressive mechanism regulating antitumor immune responses. Metabolic reprogramming and epigenetic reprogramming are interrelated, and to a large extent, metabolic state determines the epigenetics of cancer.
Metabolic pathways such as glycolysis or oxidative phosphorylation regulate macrophage function during inflammation and tissue repair, and α-ketoglutarate coordinates macrophage activation to the M2 phenotype through metabolic and epigenetic reprogramming.
Enhanced glycolysis has also been identified as an epigenetic modification affecting osteopontin gene expression. Ultimately, metabolic conditions within the TME enhance epigenetic reprogramming of cancer cells and immune cells, resulting in an immunosuppressive microenvironment, however, these epigenetic modifications exhibit plasticity that can be corrected by epigenetic regulators.
At the molecular level, key effector molecules known to be associated with immune function ( STING ), CD8+ cytotoxic T cells ( GzmB, IFN-γ, IL-2, IL-12 ), and FOXP3+ Treg cells via epigenetic pathways adjust. In fact, many cytokines and chemokines are regulated in cancer through epigenetic pathways.
Immune checkpoint molecules ( ICMs ) include PD-1, CTLA-4, TIM-3, LAG-3 and TIGIT. The expression of these molecules and their receptors on the surface of cancer cells and immune cells, or their soluble secreted forms, helps tumor cells evade immune surveillance.
Epigenetic mechanisms play a key role in regulating the expression of ICMs and their receptors in the TME. As a specific example, LAG-3 DNA methylation correlates with the expression of this immune checkpoint molecule in both tumor and immune cells, affecting the fate of immune cell infiltration in clear cell renal cell carcinoma.
Epigenetically Targeted Drugs
Epigenetic drugs are often used in combination with other immune stimulators to achieve five goals:
1) cancer cell growth arrest;
2) induction of tumor cell death ( via apoptosis, necrosis, autophagy );
3) promotion of tumor-associated neoantigens
4.) Hypoxia reversal and tumor angiogenesis inhibition;
5.) Regulation of immune cell (DC, T cell, etc.) function in TME.
Currently, a large number of small-molecule enzyme inhibitors or activators involving epigenetic regulatory pathways are being developed for clinical use. Many epigenetic drugs have received regulatory approval for the treatment of human malignancies.
In 2004, the FDA approved 5-azaC ( trade name Vidaza ) for all five stages of myelodysplastic syndrome ( MDS ), followed by 5-aza-dC in 2006. These two drugs currently represent first-line therapy for MDS when stem cell therapy is not appropriate. They are also used in the treatment of chronic myelomonocytic leukemia ( CMML ) and AML.
Some HDAC inhibitors ( HDACi ) have also been approved by the FDA for clinical use. Vorinostat and romidepsin were the first drugs in this class to be approved for the treatment of cutaneous T-cell lymphoma ( CTCL ). SAHA, also known as Zolinza or Vorinostat, was approved by the FDA in 2006 and is currently a third-line treatment option for patients with CTCL.
Romidepsin was the second HDAC inhibitor approved by the FDA in 2009. Subsequently, Belinostat and Panobinostat, along with Chidamine, were both approved for the treatment of relapsed or refractory peripheral T-cell lymphoma ( PTCL ) or multiple myeloma.
The third wave of FDA drug approvals has occurred in the past few years. In 2017 and 2018, isocitrate dehydrogenase 1 and 2 ( IDH1/2 ) inhibitors, Enasidenib and Ivosidenib, were approved for the treatment of relapsed or refractory AML, respectively.
Finally, in 2020, the FDA granted accelerated approval to tazemetostat, an inhibitor of EZH2, for the treatment of epithelioid sarcoma and relapsed/refractory follicular lymphoma.
Clinical Prospects of Epigenetic Drugs
To date, epigenetic drugs have generally not demonstrated sufficient efficacy in advanced tumors to qualify for FDA approval, with the exception of a few types of solid tumors, T-cell lymphoma, epithelioid sarcoma, and refractory follicular lymphoma or other regulatory agency approvals.
However, some clinical studies on solid tumors show promise. First, Tazemetostat is a representative of the first class of inhibitors and is effective against two solid tumors. Monotherapy demonstrated clinically meaningful, durable responses and was generally well tolerated in patients with relapsed or refractory follicular lymphoma or advanced epithelioid sarcoma after multiple treatments.
Second, the combination of two or more epigenetic drugs may be a good option to improve the antitumor efficacy of treatment. In one study, the combination of azacitidine and romidepsin with IFN-α was demonstrated to have high therapeutic potential, targeting the most aggressive cellular components of colorectal cancer ( i.e., metastatic cells and cancer stem cells ) and modulating Key survival and death pathways ( including tumor ICD ).
In another study, investigators evaluated the combination of azacitidine and entinostat in patients with relapsed metastatic NSCLC, showing objective, durable responses in some patients with refractory NSCLC.
Furthermore, in preclinical studies, EZH2 inhibitors have been reported to enhance the antitumor response of ICIs. In one case report, a patient with SMARCB1-negative chordoma treated with an EZH2 inhibitor ( tazemetostat ) had a persistent systemic response to radiation over 2 years.
Functional analysis revealed a marked increase in intratumoral and stromal infiltration of CD8+ T cells and Treg cells, which was associated with enhanced expression of PD-1 and LAG-3 checkpoint molecules on T cells.
These results suggest that EZH2 inhibition promotes a sustained antitumor immune response, leading to immune checkpoint activation. Emerging clinical data also suggest that combination therapy of epigenetic drugs and ICIs holds promise for a range of patients with solid cancers.
Currently, there are multiple clinical trials of epigenetic drugs combined with ICIs in progress.
There is compelling evidence that epigenetic regulation affects cancer cells, immune cells, stromal cells, interactions between cancer cells and immune cells, and the state of the immune TME. Thus, as an intervention, epigenetic modulation itself can induce robust antitumor immunity.
Therefore, a reasonable strategy to further enhance the efficacy of immunotherapy is to combine certain epigenetic regulators with one or more classical immunotherapy regimens, such as cancer vaccines, ICIs, oncolytic viruses, CAR-T cells, TCR- T cells or other novel immune stimulators.
Epigenetic drugs can induce ICD and turn tumors from cold to hot, and they may work synergistically with other immunotherapeutic regimens. In the future, these combination regimens may show promising application in clinical studies.
1. Epigenetic modulation of antitumor immunity for improved cancer immunotherapy. Mol Cancer. 2021; 20: 171.
What is Epigenetic regulation in tumor immunity?
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