Oncogene SET Domain Bifurcated 1 (SETDB1)/ESET, an H3K9 methyltransferase, was originally discovered over two decades ago; however, its function in the immune response was not first reported until 2011. SETDB1 immune functions include B cell maturation, T cell activity regulation, and immune escape in cancer cells. In B lymphocytes, SETDB1 mediates the transition from pro‐B to pre‐B cells and represses endogenous retroviruses (ERV) to encourage B cell lineage differentiation and maturation. SETDB1 alters T cell function by methylating IL‐2 and IL‐17 promoters and mediating T cell lineage commitment and development. In addition, SETDB1 plays a critical role in ERV silencing within a variety of immune cells, which can indirectly weaken the immune response. Although SETDB1 is critical for normal immune cell function, overexpression in cancer cells negatively impacts immune cell fights against cancer through decreased tumour immunogenicity. Within cancer cells, SETDB1 overexpression represses production and infiltration of antitumour immune cells, mediates immune escape through TE and ERV silencing, represses the type I interferon pathway, and interferes in immune checkpoint blockade (ICB) outcomes by regulation of PD‐L1 expression and IFN signalling. In this review, we further discuss the immunological mechanisms of SETDB1 in normal and cancerous cells and its implications in cancer immunotherapy.

SETDB1 is characterized as an important epigenetic regulator in many different cancers and involved in transcriptional silencing of many different processes and pathways. It is often overexpressed in many different cancers including colon, melanoma, breast and pancreatic cancers and its high expression is correlated with worse patient outcome. Often associated with repressing complexes such as HUSH and KAP1/KRAB, it has been shown to repress many different genes such as p53 and p21 through histone H3K9 methylation. In addition, it has been implicated in regulating transposable elements (TEs), primarily of the LTR types as well as SINEs and LINEs. Activation of TEs is key to induction of anti-viral response genes such as the type I interferon pathway and immune-stimulated genes (ISGs) which in turn promote innate immune response against the tumor. Here, we show that SETDB1 promotes tumor growth in endometrial cancer possibly through establishing an immune evasion from the innate immune system. Mice subcutaneously injected with SETDB1 depleted endometrial cancer cells show prolonged survival time and reduced tumorigenesis. In NSG mice, we demonstrate that subcutaneously injected endometrial cancer cell, ISHIKAWA, shows both increased penetration and recruitment of macrophages in the tumor when SETDB1 is knocked out. Our macrophage-cancer cells co-culture in-vitro assay suggests that macrophages induce greater killing in SETDB1-/- cells when stimulated into M1 phenotype more so than in WT cancer cells. Further, tumor IHC analysis shows greater proliferation capacity for control tumor relative to SETDB1-/- as evident by greater mitotic figures per unit area and Ki67 staining score. We further show that cytokines such as CCL5 and CXCL9 (previously reported for their positive correlation with T-cell infiltration in tumor) are significantly upregulated in SETDB1 knockout tumors relative to non-targeting control tumors (NT) as well as in cell lines. Endometrial cancer TCGA data show significant negative correlation between SETDB1 and markers of T-cell infiltration such as CD8A and IFNG as well as cytokines CCL5 and CXCL9. Overall, these findings show important implication of SETDB1 in macrophage recruitment and macrophage-mediated killing of cancer cells in addition to its role in promoting tumor cells proliferation. Citation Format: Kiarash Salari, Matthew Wells, Eleanor R. Johnson, Tianyue Li, Jiaqing Hao, Bing Li, Shujie Yang. Understanding SETDB1-mediated tumor immune evasion mechanism in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 675.