Overcoming Immune Checkpoint Blockade Resistance via EZH2 Inhibition

Immune checkpoint blockade (ICB) has revolutionized the current cancer treatment paradigm, but low response rates require combination strategies to overcome primary and acquired ICB resistance. Enhancer of zeste homolog 2 (EZH2) influences several key aspects of the tumor microenvironment that can contribute to ICB resistance, making it an attractive target to overcome ICB resistance in the clinic. EZH2 inhibition can lead to increased T regulatory cell trafficking, impaired T regulatory cell capacity, increased antigen presentation, and increased antitumor immunity. EZH2 inhibition has potentiated ICB in several preclinical models and can overcome acquired resistance to ICB in preclinical models of prostate cancer and head and neck cancer. Additional studies are needed to understand the full potential of EZH2 inhibition as a possible strategy to improve antitumor immunity. EZH2 inhibition in combination with ICB is currently being evaluated in the clinic. Recent progress in cancer immunotherapy highlights the power of the immune system to control tumors, although a small patient subset responds to current immunotherapies. Additional approaches to mobilize antitumor immunity are required to overcome primary and acquired resistance to immunotherapy such as immune checkpoint blockade (ICB). Emerging evidence shows that targeting epigenetic elements that promote tumor progression and inhibit immune cell activity can enhance antitumor immunity by reshaping the tumor microenvironment (TME). Here, we review the pleiotropic functions in tumor and immune cells of enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), with a focus on EZH2 inhibition as a potentially promising approach to enhance current immunotherapies and improve patient outcomes for certain cancers. Recent progress in cancer immunotherapy highlights the power of the immune system to control tumors, although a small patient subset responds to current immunotherapies. Additional approaches to mobilize antitumor immunity are required to overcome primary and acquired resistance to immunotherapy such as immune checkpoint blockade (ICB). Emerging evidence shows that targeting epigenetic elements that promote tumor progression and inhibit immune cell activity can enhance antitumor immunity by reshaping the tumor microenvironment (TME). Here, we review the pleiotropic functions in tumor and immune cells of enhancer of zeste homolog 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), with a focus on EZH2 inhibition as a potentially promising approach to enhance current immunotherapies and improve patient outcomes for certain cancers. comprise a heterogeneous population of cells involved in tissue remodeling to support cancer invasion and metastasis; support immune tolerance within the TME by promoting suppressive cells and eradicating effector cells. chimeric antigen receptor T cells genetically modified to contain a TCR that specifically targets antigens within a patient’s tumor. further differentiate into multiple Th subsets (Th1, Th2, and Th17) in response to developmental and environmental cues. characterized by their ability to suppress immune responses by other cells; express CD25, reflecting their sensitivity to survival factor IL-2; also express Foxp3. epigenetic modifications are involved in the transition from naïve T cells to CD8+ Tmem cells; some of these modifications persist after antigen clearance, establishing epigenetic memory that allows faster activation upon re-encounter with antigen. Certain effector genes, for example, IFNG, are not expressed but are transcriptionally poised for fast expression upon activation. human gene (chromosome 9, band p21.3) is ubiquitously expressed in many tissues and cell types; codes for two proteins, INK4 family members p16 and p14ARF, which act as tumor suppressors by regulating the cell cycle. Somatic mutations of CDKN2A are common in most human cancers; germline mutations of CDKN2A are associated with familial melanoma, glioblastoma, and pancreatic cancer. portion of a protein important in regulating protein degradation rates. Known degrons include short amino acid sequences, structural motifs, and exposed amino acids (often lysine or arginine) located anywhere in the protein. antigen-presenting cells of the mammalian immune system whose primary function is to process and present antigen to the surface of T cells, acting as messengers between the innate and adaptive immune systems. DCs are usually not abundant at tumor sites, but increased densities of DC populations have been associated with improved clinical outcomes for certain cancers. family of enzymes catalyzing the transfer of a methyl group to DNA, serving a wide variety of biological functions. Due to their epigenetic effects, some DNMT inhibitors are under investigation for certain cancer treatments. developed by deleting, overexpressing, or mutating genes known to be strongly associated with a specific condition; here, tumor formation. Useful for immunotherapy assessment because of their fully competent immunity and their similarity to human tumor growth. form of post-translational modification of histone proteins, including methylation, phosphorylation, acetylation etc., regulating gene expression by altering chromatin structure. immune checkpoints include a number of inhibitory pathways hardwired into the immune system for maintenance of self-tolerance and modulation of the immune response to microbes and tumors. Many depend on ligand–receptor engagement, such as PD-L1–PD1 or B7.1(2)–CTLA-4. Antibody blockade of these interactions can enhance immune responses. Anti-CTLA-4 and anti-PD-1 are antibody prototypes of this class of cancer ICB immunotherapeutics. T cells that recognize self and foreign lipid antigens in the context of CD1d (nonpolymorphic MHC-I-like molecule) and express effector cytokines, including IFNγ and IL-4 within minutes after antigen recognition. The vast majority of iNKT cells express T cell receptor (TCR)α (Vα14/Jα18 in mice; Vα24/Jα18 in humans) paired with a restricted set of TCRβ, and thus are considered invariant. CD4+ Tregs generated from conventional CD4+ T cells in vitro with conditions that induce FoxP3 expression, including stimulation with (i) anti-CD3, anti-CD28 antibodies, IL-2, and transforming growth factor-β (Tgf-β) and (ii) anti-CD3 antibodies, Tgf-β, and DCs. cell surface molecules that present peptides derived from protein antigens to CD8+ or CD4+ T cells respectively. MHC class I is expressed ubiquitously while MHC class II is expressed in general by professional antigen-presenting cells, including B cells and DCs. heterogeneous population of cells consisting of immature myeloid cells; expand during cancer, inflammation, and infection, and display a remarkable ability to suppress T cell responses. type of cytotoxic lymphocytes of the innate immune system with antiviral, anticancer, and anti-graft-versus-host disease properties. developed in non-lymphoid tissues at sites of chronic inflammation (including tumors) and affected tissues in patients with autoimmune disease. specialized CD4+ T cell subset; provides help to B cells triggering them to produce antibodies within germinal centers in secondary lymphoid structures. designed to treat existing tumors through stimulation of the immune system with cancer antigens or autologous tumor cells from a patient. epigenetic modification to the chromatin structure protein histone H3; associated with repression of gene transcription via the formation of heterochromatic regions. present on some tumor cells and also some normal cells; can trigger an immune response in the host; are useful markers for identifying tumor cells with diagnostic tests and potential target candidates in cancer therapy. contribute to tumor initiation, progression, and metastasis by inhibiting T-cell mediated immunity and stimulating tumor angiogenesis; generally characterized by expression of anti-inflammatory cytokines, scavenging receptors, angiogenic factors, and proteases; together, contribute to an immunosuppressive TME. subpopulation migrating to tumors, recognizing and attacking cancer cells upon infiltration. High numbers of TILs in tumors may be indicative of an improved clinical outcome. interactive cellular milieu surrounding a tumor; includes blood vessels, immune cells, cytokines and chemokines, fibroblasts, and the extracellular matrix.