Downregulation of MUC1 expression and its recognition by CD8⁺ T cells on the surface of malignant pleural mesothelioma cells treated with HDACi.

Research into new treatments against malignant pleural mesothelioma (MPM) is of great interest, as this aggressive cancer is often resistant to conventional therapies. One potential strategy is the use of epigenetic drugs, such as 5-aza-2'-deoxycytidine (5-azaCdR), a DNA-hypomethylating drug, and valproate (VPA), a histone deacetylase inhibitor (HDACi). Indeed, these drugs not only trigger MPM cell death, but also induce the expression of cancer testis antigens recognized by CD8(+) T cells, such as New York-esophageal cancer-1 (NY-ESO-1). The objective of this study was to assess effects of these drugs on the expression and recognition by CD8(+) T cells of Mucin1 (MUC1), a tumor-associated antigen that is overexpressed by MPM. MPM tumor cell lines were treated with epigenetic drugs, alone or in combination. MUC1 expression by MPM cells, and its recognition by a MUC1-specific CD8(+) T-cell clone, was downregulated by HDACi when used alone or in combination with 5-azaCdR. This effect was not due to a blocking of the HLA class I presentation pathway in treated MPM cells, as NY-ESO-1 induced by 5-azaCdR alone, or with VPA, was recognized by a NY-ESO-1-specific T-cell clone. This study suggests that the choice of tumor antigens could be critical for strategies combining epigenetic drugs with immunotherapy.