The polycomb group proteins, BMI-1 and EZH2, are tumour-associated antigens

Abstract

We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8 þ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-g (IFN-g) release than BMI-1-derived peptides. That CD8 þ T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-g capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666 -674) epitope. The ability of YMSCSFLFNL (aa 666 -674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25 þ T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.

Results of donor lymphocyte infusions for relapsed myelodysplastic syndrome after hematopoietic cell transplantation

“…The aberrant expression of WT1 in BM of MDS patients is frequently associated with cellular 29,30 and humoral 31,32 WT1-specific immune responses. Humoral and cellular autoimmune responses have also been detected against BMI1 in patients with hepatocellular carcinoma, 33 and against PRAME in AML patients. 34 One could speculate that the superior response to DLI observed in the high-risk IPSS patients might be related to the higher expression of tumor-associated antigens in this group, which could render the neoplastic clone more susceptible to immunologic attack after DLI.…”

BMI-1 autoantibody in serum as a new potential biomarker of nasopharyngeal carcinoma

“…Recently, BMI-1 overexpression has been identified as a marker of poor prognosis and metastasis in breast cancer, 12 acute myeloid leukemia 13 and neuroblastoma. 14 Notably, BMI-1 is associated with both humoral and T-cell responses, [15][16][17] suggesting that it represents a novel family of tumor-associated antigens(TAAs) that might be a potential target for immunotherapy.…”

Epigenetic regulation of normal and malignant hematopoiesis

“…Indeed, downregulation of the polycomb component EED is associated with an increase incidence of carcinogen-induced lymphoma (Richie et al, 2002). Similarly, dysregulation of BMI1 also affects the activity of the PRCs, and overexpression and overactivity of BMI1 has been associated with a variety of solid tumors including lung, breast, colon, prostate and neuroblastoma as well as in malignant hematopoiesis (Breuer et al, 2004;Glinsky et al, 2005;Steele et al, 2006). Given its critical role in normal stem cell function, it seems likely that BMI1 plays an important role in the ability of the cancer cell to undergo limitless self-renewal (Lessard and Sauvageau, 2003).…”