INSERM, Institut de Recherche Thérapeutique de l'Université de Nantes, France.
Eur J Immunol. 2012 Mar;42(3):783-9. doi: 10.1002/eji.201141800. Epub 2012 Jan 13.
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.
研究针对恶性胸膜间皮瘤 (MPM) 的新治疗方法非常有趣，因为这种侵袭性癌症通常对传统疗法具有抗性。一种潜在的策略是使用表观遗传药物，例如 5-氮杂-2'-脱氧胞苷 (5-azaCdR)，一种 DNA 低甲基化药物，和丙戊酸 (VPA)，一种组蛋白去乙酰化酶抑制剂 (HDACi)。事实上，这些药物不仅能引发 MPM 细胞死亡，还能诱导 CD8(+) T 细胞识别的癌症睾丸抗原的表达，如纽约食管癌抗原-1 (NY-ESO-1)。本研究的目的是评估这些药物对 Mucin1（MUC1）表达和 CD8(+) T 细胞识别的影响，MUC1 是 MPM 过度表达的肿瘤相关抗原。单独或联合使用表观遗传药物处理 MPM 肿瘤细胞系。HDACi 单独或与 5-azaCdR 联合使用时，下调 MPM 细胞的 MUC1 表达及其被 MUC1 特异性 CD8(+) T 细胞克隆的识别。这种作用不是由于处理的 MPM 细胞中 HLA Ⅰ类呈递途径被阻断，因为 5-azaCdR 单独诱导或与 VPA 联合诱导的 NY-ESO-1 被 NY-ESO-1 特异性 T 细胞克隆识别。本研究表明，在将表观遗传药物与免疫疗法联合使用的策略中，肿瘤抗原的选择可能是关键的。
