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

Abstract

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 0 -deoxycytidine (5-azaCdR), a DNAhypomethylating 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 1 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 1 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 1 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.

Valproic acid attenuates CCR2-dependent tumor infiltration of monocytic myeloid-derived suppressor cells, limiting tumor progression

“…Among the four classes of HDACs, VPA preferentially inhibits class I HDACs (HDAC1, 2, 3, and 8). 27 Although VPA has been reported to directly inhibit tumor cell proliferation and attenuate tumor immunogenicity via HDAC inhibition, 28,29 the immune regulation ability of VPA in the TME has rarely been addressed. In this study, we clearly showed that VPA could effectively relieve the immunosuppressive TME through a reduction in tumor-infiltrating M-MDSCs, leading to a reduction of tumor burden ( Figure 6(e)).…”

Is there a Role for Epigenetic Enhancement of Immunomodulatory Approaches to Cancer Treatment?

“…For example, zebularine, via the upregulation of IDO, has also been shown to decrease immunogenicity, but only at high doses; at low doses, the immunogenicity is increased [102]. The balance between activated and repressing immunological response appears to be both cell and agent specific, as HDAC inhibition has been shown to both increase expression of tumour associated antigens, for example gp100 in murine melanoma cells [103], and in other systems to downregulate tumour antigens, for example Muc1 in mesothelioma cells [104]. This highlights the complex nature of epigenetic modulation, and the likelihood that it will not work as expected in all cancers or all individuals.…”

Combining targeted therapy with immunotherapy. Can 1+1 equal more than 2?

“…Histone deacetylase (HDAC), on the other hand, removes acetyl groups and suppresses the gene transcription process. HDAC inhibitors have been shown to restore expression of TAA and cancer-testis antigens such as NY-ESO-1 (61–63), enhance MHC class I and II expression(64, 65), and upregulate PD-L1 expression(66, 67). In preclinical models, Kim et al reported tumor eradication in 80% of mice bearing either CT26 colon cancer or 4T1 breast cancer, treated with combination of epigenetic-modulators (5-AZA plus entinostat, a HDAC inhibitor) and checkpoint inhibitors (anti-CTLA4 plus anti-PD1), but not checkpoint inhibitors alone, accomplished by depletion of myeloid derived suppressive cells (MDSC) (68).…”