Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo
Inhibitors of apoptosis confer resistance to tumour suppression by adoptively transplanted cytotoxic T-lymphocytes in vitro and in vivo
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DOI：
10.1038/sj.cdd.4401563
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发表时间：
2005-04-01
影响因子：
12.4
通讯作者：
Schuler, M
中科院分区：
文献类型：
--
作者：
Huber, C;Bobek, N;Schuler, M
细胞凋亡信号的解除调控在癌症中很常见，并导致对细胞毒治疗的抵抗。免疫疗法是消除耐药癌细胞的一种很有前途的策略。异基因干细胞移植过程中T淋巴细胞的转移在临床上被用来诱导“移植物抗肿瘤”效应(GVT)。细胞毒性T淋巴细胞(CTL)是GVT的主要效应者，通过多条平行途径诱导细胞凋亡，从而清除肿瘤细胞。在这里，我们在体外和体内研究了表达单一抗凋亡基因的小鼠癌细胞对CTL介导的细胞毒的敏感性。有趣的是，我们发现caspase激活的单一抑制剂，如bclxl或FADD和caspase-9的显性阴性突变体，在体外可以保护癌细胞免受抗原特异性CTL的攻击。此外，bclxl的表达削弱了体内过继移植CTL对已建立的肿瘤的生长抑制作用。因此，为细胞毒性癌症治疗提供保护的细胞凋亡缺陷可以通过肿瘤反应性CTL对免疫治疗产生交叉耐药。
Deregulation of apoptosis signalling is commonly found in cancer and results in resistance to cytotoxic therapies. Immunotherapy is a promising strategy to eliminate resistant cancer cells. The transfer of T-lymphocytes during allogeneic stem cell transplantation is clinically explored to induce a 'graft-versus-tumor' effect (GvT). Cytotoxic T-lymphocytes (CTL), which are major effectors of GvT, eliminate cancer cells by inducing apoptosis via multiple parallel pathways. Here, we study in vitro and in vivo the susceptibility of murine cancer cells engineered to express single antiapoptotic genes to CTL-mediated cytotoxicity. Interestingly, we find that single inhibitors of caspase activation, such as BCL-XL or dominant-negative mutants of FADD and caspase-9, protect cancer cells against antigen-specific CTL in vitro. Moreover, expression of BCL-XL impairs the growth suppression by adoptively transplanted CTL of established tumours in vivo. Hence, apoptosis defects that provide protection to cytotoxic cancer therapies can confer crossresistance to immunotherapy by tumour-reactive CTL.