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Inhibition of histone methyltransferase EZH2 for immune-interception of colorectal cancer in Lynch syndrome

ABSTRACT: This study investigates the potential of EZH2 inhibition as a preventive strategy for colorectal cancer in Lynch Syndrome (LS) by modulating the immune system. Using a mouse model of LS and colonic organoids, researchers treated the mice with the EZH2 inhibitor GSK503 and observed increased CD4+ and CD8+ T cells in both spleen and colon tissue. Over a 9-week period, the inhibitor reduced adenoma formation, indicating its preventive efficacy. RNA sequencing and ChIPseq analyses revealed that EZH2 inhibition activated immune and apoptotic markers and decreased H3K27 methylation, leading to changes in gene regulation. These findings suggest that EZH2 inhibitors hold promise for cancer prevention in LS by reprogramming immune responses and gene expression patterns.

ORGANISM(S): Mus musculus

PROVIDER: GSE277940 | GEO | 2025/02/14

REPOSITORIES: GEO

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Inhibition of Histone Methyltransferase EZH2 for Immune-Interception of Colorectal Cancer in Lynch Syndrome

Project description:This study investigates the potential of EZH2 inhibition as a preventive strategy for colorectal cancer in Lynch Syndrome (LS) by modulating the immune system. Using a mouse model of LS and colonic organoids, researchers treated the mice with the EZH2 inhibitor GSK503 and observed increased CD4+ and CD8+ T cells in both spleen and colon tissue. Over a 9-week period, the inhibitor reduced adenoma formation, indicating its preventive efficacy. RNA sequencing and ChIPseq analyses revealed that EZH2 inhibition activated immune and apoptotic markers and decreased H3K27 methylation, leading to changes in gene regulation. These findings suggest that EZH2 inhibitors hold promise for cancer prevention in LS by reprogramming immune responses and gene expression patterns.

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Project description:Objectives: Specific Aims: 1. Researchers will evaluate and compare predictors of health-related quality of life (QOL) among colorectal cancer (CRC) survivors who have Lynch syndrome (LS) with those patients who have sporadic CRC using both quantitative and qualitative methodology. a. In both CRC groups, researchers will evaluate cancer preventive and health behaviors, including lifestyle factors and screening, psychosocial factors, including mood, family functioning, coping style, anxiety, depression, and social resources, and health care system factors, including interactions with health care providers and service utilization. 2. Researchers will compare the experience of first-degree relatives (FDRs) of patients who have LS with that of FDRs of patients who have sporadic CRC using both quantitative and qualitative methodology. a. Researchers will evaluate all of the domains listed above, as well as anticipatory grief, assessment of caregiving responsibilities, and fear of cancer in FDRs of patients with LS-related and sporadic CRC. 3. Researchers will examine CRC patients from both groups and their FDRs using dyadic analyses in order to evaluate the similarities and differences in their survivorship experience. 4. Researchers will evaluate the preventive and health behavior of patients who are non-conclusive for Lynch syndrome and their family members. They will examine their screening behavior and will explore how the interaction between the patients and their relatives affects the relatives’ screening behavior. They also will examine how these non conclusive LS patients and their family members perceive their risk for LS-related cancers.

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Project description:Lynch syndrome (LS) patients develop DNA mismatch repair deficient tumors which generate high loads of neoantigens (neoAgs), thus constituting a well-defined population that can benefit from cancer immune-interception strategies, including neoantigen-based vaccines. Using paired whole-exome sequencing and mRNAseq of colorectal cancers (CRC) (n=13) and pre-cancers (n=61) from our LS patient cohort (N=46), we performed in-silico prediction and immunogenicity ranking of highly recurrent frameshift-neoags, followed by their in-vitro validation. We described the somatic mutation landscape in all cancers and pre-cancers, and showed that mutation burden is positively correlated with neoAgs load. Furthermore, our in-vitro validation showed a 65% validation rate of our top 100 predicted neoags. Consistent with neoAgs burden, our transcriptomic results revealed increased infiltration of CD8+ and CD4+ T-cells in microsatellite unstable samples. Overall, our neoAgs catalog and all other findings, improve our understanding of cancer development in LS and guide us towards the advancement of immunoprevention vaccine strategies.

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