Department of Tumour Immunology, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4 14220, Czech Republic.
Br J Cancer. 2011 Nov 8;105(10):1533-41. doi: 10.1038/bjc.2011.428. Epub 2011 Oct 20.
Epigenetic mechanisms have important roles in the tumour escape from immune responses, such as in MHC class I downregulation or altered expression of other components involved in antigen presentation. Chemotherapy with DNA methyltransferase inhibitors (DNMTi) can thus influence the tumour cell interactions with the immune system and their sensitivity to immunotherapy.
We evaluated the therapeutic effects of the DNMTi 5-azacytidine (5AC) against experimental MHC class I-deficient and -positive tumours. The 5AC therapy was combined with immunotherapy, using a murine model for HPV16-associated tumours.
We have demonstrated 5AC additive effects against MHC class I-positive and -deficient tumours when combined with unmethylated CpG oligodeoxynucleotides or with IL-12-producing cellular vaccine. The efficacy of the combined chemoimmunotherapy against originally MHC class I-deficient tumours was partially dependent on the CD8(+)-mediated immune responses. Increased cell surface expression of MHC class I cell molecules, associated with upregulation of the antigen-presenting machinery-related genes, as well as of genes encoding selected components of the IFNγ-signalling pathway in tumours explanted from 5AC-treated animals, were observed.
Our data suggest that chemotherapy of MHC class I-deficient tumours with 5AC combined with immunotherapy is an attractive setting in the treatment of MHC class I-deficient tumours.
表观遗传机制在肿瘤逃避免疫反应中起着重要作用，例如 MHC I 类下调或参与抗原呈递的其他成分表达改变。因此，用 DNA 甲基转移酶抑制剂 (DNMTi) 进行化疗可以影响肿瘤细胞与免疫系统的相互作用及其对免疫治疗的敏感性。
我们评估了 DNA 甲基转移酶抑制剂 5-氮杂胞苷 (5AC) 对实验性 MHC I 缺陷和阳性肿瘤的治疗效果。该 5AC 治疗与免疫治疗相结合，使用 HPV16 相关肿瘤的小鼠模型。
我们已经证明，当与未甲基化的 CpG 寡脱氧核苷酸或 IL-12 产生的细胞疫苗联合使用时，5AC 对 MHC I 阳性和缺陷肿瘤具有相加作用。针对最初 MHC I 缺陷肿瘤的联合化疗免疫治疗的疗效部分依赖于 CD8(+)介导的免疫反应。从接受 5AC 治疗的动物中取出的肿瘤中观察到 MHC I 细胞分子的细胞表面表达增加，与抗原呈递机制相关基因的上调以及 IFNγ 信号通路的选定成分的基因表达上调相关。
我们的数据表明，用 5AC 联合免疫疗法对 MHC I 缺陷肿瘤进行化疗是治疗 MHC I 缺陷肿瘤的一种有吸引力的方法。
