An epigenetically altered tumor cell vaccine
An epigenetically altered tumor cell vaccine
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DOI：
10.1007/s00262-004-0513-0
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发表时间：
2004-08-01
影响因子：
5.8
通讯作者：
Tomasi, TB
中科院分区：
文献类型：
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作者：
Khan, ANH;Magner, WJ;Tomasi, TB
对免疫至关重要的基因的功能失活可能通过突变和/或抑制发生，后者可能是通过改变染色质的试剂而可逆的。这项研究是为了确定通过改变染色质的乙酰化状态来逆转基因沉默是否可能导致有效的肿瘤疫苗。我们发现，在体外用组蛋白脱乙酰酶抑制剂曲古抑素A(TSA)处理肿瘤细胞，可以改变对肿瘤免疫至关重要的特定基因的表达，包括MHC II类、CD40和B7-1/2。在体外用TSA处理的肿瘤细胞显示，在70%的J558浆细胞瘤和100%的B16黑色素瘤注射动物中，肿瘤起病和肿瘤生长速度延迟。在两种肿瘤模型中，约有30%的野生型细胞能激发长期的肿瘤特异性免疫来重新攻击。免疫小鼠脾T细胞裂解未经处理的肿瘤细胞，而SCID小鼠未表现出免疫反应，提示T细胞可能参与免疫。我们假设免疫基因的抑制参与了肿瘤对免疫的逃避，并建议进一步探索表观遗传改变的癌细胞作为诱导肿瘤免疫的策略。
Functional inactivation of genes critical to immunity may occur by mutation and/or by repression, the latter being potentially reversible with agents that modify chromatin. This study was constructed to determine whether reversal of gene silencing, by altering the acetylation status of chromatin, might lead to an effective tumor vaccine. We show that the expression of selected genes important to tumor immunity, including MHC class II, CD40, and B7-1/2 are altered by treating tumor cells in vitro with a histone deacetylase inhibitor, trichostatin A (TSA). Tumor cells treated in vitro with TSA showed delayed onset and rate of tumor growth in 70% of the J558 plasmacytoma and 100% of the B16 melanoma injected animals. Long-term tumor specific immunity was elicited to rechallenge with wild-type cells in approximately 30% in both tumor models. Splenic T cells from immune mice lysed untreated tumor cells, and SCID mice did not manifest immunity, suggesting that T cells may be involved in immunity. We hypothesize that repression of immune genes is involved in the evasion of immunity by tumors and suggest that epigenetically altered cancer cells should be further explored as a strategy for the induction of tumor immunity.