Epigenetic mechanisms of tumor resistance to immunotherapy

Abstract

The recent impact of cancer immunotherapies has firmly established the ability and importance of the immune system to fight malignancies. However, the intimate interaction between the highly dynamic tumor and immune cells leads to a selection process driven by genetic and epigenetic processes. As the molecular pathways of cancer resistance mechanisms to immunotherapy become increasingly known, novel therapeutic targets are being tested in combination with immune-stimulating approaches. We here review recent insights into the molecular mechanisms of tumor resistance with particular emphasis on epigenetic processes and place these in the context of previous models.

Keywords: CTLA-4; Checkpoint inhibitor; Cytokine; EED; EZH2; IL-2; Immunogenicity; PD-1; PRC2; Tumor escape.

Fig. 1

Epigenetic mechanisms leading to loss of immunogenicity. a Tumor cell (black) maintains expression of tumor-associated antigens (TAA) and immune-related processes, such as antigen presentation machinery, interferon (IFN)-γ receptor, and chemokines CXCL9 and CXCL10. This leads to the accumulation of CD8⁺ T-cells (blue) in the tumor microenvironment and subsequent recognition of tumors via the major histocompatibility complex class-I (MHC-I)—TAA—T-cell receptor (TCR) complex. Infiltrating CD8⁺ and CD4⁺ T-cells (not shown) produce IFN-γ, which further promotes antigen presentation and expression of programmed death-ligand 1 (PD-L1) on tumor cells. Persistent antigen stimulation, interaction of programmed cell death protein-1 (PD-1) and PD-L1 and expression of other inhibitory signals lead to exhaustion of CD8⁺ T-cells. b Tumor cell (gray) loses the expression of the above-mentioned genes due to DNA and histone methylation. Lack of T-cell-attracting chemokines and antigen presentation inhibits T-cell infiltration and tumor recognition

Fig. 2

Polycomb repressive complex 2-mediated transcriptional repression. The polycomb repressive complex 2 (PRC2) is made of the core components enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED), and suppressor of zeste 12 (SUZ12). These associate with other subunits, such as RBAP46 (also termed RBBP7), RBAP48 (RBBP4), Jumonji and AT-rich interaction domain containing 2 (JARID2; not shown), AE binding protein 2 (AEBP2; not shown) and polycomb-like proteins (PCL; not shown). The PRC2 complex binds to unmethylated cytosin-guanine dinucleotide (CpG) islands and, via tri-methylation of lysine 27 in histone 3 (H3K27m3) of adjacent nucleosomes, mediates silencing of repressed genes

Fig. 3

EZH2-mediated immune resistance in anti-tumor immune responses. EZH2 expression (left) mediates downregulation of T-cell-attracting chemokines resulting in decreased T-cell infiltration to the tumor site. The lack of antigen presentation limits T-cell effector functions. Upon EZH2 blockade (right), expression of CXCL9 and CXCL10 increases and promotes CD8⁺ T-cell (blue) infiltration. The recognition of cancer cells by CD8⁺ T cell through the MHC-I–TAA–TCR complex leads to the secretion of effector molecules, such as perforin and granzymes (dark red). CD4⁺ T cells (orange) require EZH2 for their differentiation and maintenance. Thus, the function of Th1 cells and regulatory T (Treg) cells can be altered upon EZH2 blockade, including production of IFN-γ, interleukin-10 (IL-10) and transforming growth factor-β (TGF-β). EZH2 is important for infiltration of dendritic cells (DCs; purple) to the inflammatory microenvironment. However, EZH2-dependent downregulation of TAA affects DC-mediated priming of T-cells. Natural killer (NK) cells (red) mature and show enhanced lytic activity upon EZH2 inhibition. In summary, although EZH2 inhibition can affect DC migration and Th1 cell function, different mechanisms involved in tumor resistance can be efficiently reversed, thus improving tumor control