Epigenetic regulation of major histocompatibility complexes in gastrointestinal malignancies and the potential for clinical interception

Abstract

Background: Gastrointestinal malignancies encompass a diverse group of cancers that pose significant challenges to global health. The major histocompatibility complex (MHC) plays a pivotal role in immune surveillance, orchestrating the recognition and elimination of tumor cells by the immune system. However, the intricate regulation of MHC gene expression is susceptible to dynamic epigenetic modification, which can influence functionality and pathological outcomes.

Main body: By understanding the epigenetic alterations that drive MHC downregulation, insights are gained into the molecular mechanisms underlying immune escape, tumor progression, and immunotherapy resistance. This systematic review examines the current literature on epigenetic mechanisms that contribute to MHC deregulation in esophageal, gastric, pancreatic, hepatic and colorectal malignancies. Potential clinical implications are discussed of targeting aberrant epigenetic modifications to restore MHC expression and 0 the effectiveness of immunotherapeutic interventions.

Conclusion: The integration of epigenetic-targeted therapies with immunotherapies holds great potential for improving clinical outcomes in patients with gastrointestinal malignancies and represents a compelling avenue for future research and therapeutic development.

Keywords: Cancer immune evasion; Epigenetic regulation; Gastrointestinal cancer; Immunotherapy; MHC.

Fig. 1

Transcriptional and epigenetic modulation of MHC class I and class II genes by MHC-I/II enhanceosomes. a MHC-I enhanceosome recruits HATs and HMTs to MHC-I class I gene promoter regions inducing the expression of MHC-I antigen presentation pathway (APP)-associated genes. b MHC-II enhanceosome-induced DNA looping facilitates HAT and AMT recruitment into the proximal promoter of MHC class II genes enabling MHC-II APP-associated gene induction. IFN-γ, interferon-gamma; HAT, histone acetyltransferase; HMT, histone methyltransferase; AMT, arginine methyltransferase; IRF-1, interferon regulatory factor 1; ISRE, interferon-sensitive response element; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STAT1, signal transducer and activator of transcription 1, CDK7; cyclin-dependent kinase 7; RNA Pol II, RNA polymerase II; TATA, Goldberg–Hogness (TATA) box. Panel (a) adapted from Jongsma MLM et al., Mol Immunol 2019;113:17 and Panel (b) adapted from Masternak K et al., Genes Dev 2000;14(9): 1159. Created with BioRender.com on April 24, 2024

Fig. 2

MHC-I and MHC-II expression in gastric normal and cancer tissues. a, c Heterogeneous expression of HLA-DRA and HLA-B proteins in human tissue microarrays (TMAs). b, d Kaplan–Meier (KM) curves for HLA-DRA and HLA-B gene expression in gastric cancer. For quantification of percent labeling in TMAs see https://www.proteinatlas.org/

Fig. 3

MHC-II-related expression in pancreatic normal and cancer tissues. a Weak-to-moderate CIITA protein expression in human TMAs. b KM survival curves for CIITA gene expression in pancreatic cancer. For quantification of percent labeling in TMAs see https://www.proteinatlas.org/

Fig. 4

Epigenetic landscapes and chromatin accessibility of MHC-I and MHC-II genes in human colon cancer cells. Chromatin immunoprecipitation sequencing (ChIP-seq) in HCT116 cells for histone H3K27ac and H3K27me3, or reduced-representation bisulfite sequencing for DNA methylation, with color coding representing methylated CpG island density (fold-change vs. normal). cCREs, cis-regulatory elements (red promoter-like; orange proximal enhancer-like; yellow distal enhancer-like); ATAC-seq, assay for transposase-accessible chromatin with sequencing. Data from the UCSC Genome Browser (https://genome.ucsc.edu) and ENCODE (https://www.encodeproject.org)

Fig. 5

KM survival curves for colorectal cancer patients with high vs. low MHC-I (top and middle panels) and MHC-II gene expression (lower panels). Data obtained from the Human Protein Atlas (https://www.proteinatlas.org/)

Fig. 6

MHC-I and MHC-II expression in colorectal normal and cancer tissues. a, c Heterogeneous expression of HLA-DRA and B2M proteins in human TMAs. b, d KM survival curves for HLA-DRA and B2M gene expression in colorectal cancer. For quantification of percent labeling in TMAs see https://www.proteinatlas.org/

Fig. 7

MHC-I and MHC-II expression in head and neck cancer and normal tissues. a, c Heterogeneous expression of HLA-DRB1 and LMP7 proteins in human TMAs. b, d KM survival curves for HLA-DRB1 and LMP7 gene expression in head and neck cancer. For quantification of percent labeling in TMAs see https://www.proteinatlas.org/

Fig. 8

MHC-I and MHC-II expression in hepatic normal and cancer tissues. a, c Heterogeneous expression of CIITA and B2M proteins in human TMAs. b, d KM survival curves for CIITA and B2M gene expression in liver cancer. For quantification of percent labeling in TMAs see https://www.proteinatlas.org/

Fig. 9

Epigenetic Regulation of MHC-I and MHC-II in gastrointestinal cancer. Epigenetic mechanisms and drugs affecting MHC-I and MHC-II expression in gastrointestinal cancer cells, including histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, as well as the possible role of histone methyltransferase (HMT) inhibitors. IFN-γ, interferon-gamma; IL-2, interleukin-2; GrB, Granzyme B; Prf, Perforin; PRC2i, PRC2 inhibitors; WDR5i, WDR5 inhibitors. Created with BioRender.com