Ectopic expression of X-linked lymphocyte-regulated protein pM1 renders tumor cells resistant to antitumor immunity.
Ectopic expression of X-linked lymphocyte-regulated protein pM1 renders tumor cells resistant to antitumor immunity.
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DOI：
10.1158/0008-5472.can-09-3856
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发表时间：
2010-04-15
期刊：
影响因子：
11.2
通讯作者：
Kim TW
中科院分区：
文献类型：
--
作者：
Kang TH;Noh KH;Kim JH;Bae HC;Lin KY;Monie A;Pai SI;Hung CF;Wu TC;Kim TW
肿瘤免疫逃逸是癌症免疫治疗的主要障碍，但所涉及的机制仍然知之甚少。我们先前已经使用体内免疫选择策略开发了免疫逃避肿瘤模型，并揭示了Akt介导的对由各种癌症免疫抑制剂诱导的抗肿瘤免疫的免疫抗性。在目前的研究中，我们采用微阵列基因分析，以确定Akt激活的候选分子在免疫耐药肿瘤中过表达相比，父母的肿瘤。X-连锁淋巴细胞调节蛋白pM 1（XLR）基因在免疫耐药肿瘤中的表达最高。此外，亲本肿瘤细胞中XLR的逆转录病毒转导导致Akt的活化，导致抗凋亡蛋白的上调和亲本肿瘤细胞中免疫抗性表型的诱导。此外，我们发现用来自小鼠XLR家族的其他同源基因，如联会复合物蛋白3（SCP 3）和XLR相关的减数分裂调节蛋白（XMR）及其人类对应物SCP 3（hSCP 3）转导亲本肿瘤细胞也导致Akt活化，从而导致抗凋亡蛋白的上调和免疫抗性表型的诱导。重要的是，一组人宫颈癌的表征揭示了与正常宫颈组织相比，人宫颈癌组织中hSCP 3的表达水平相对较高。因此，我们的数据表明，XLR及其同源物在肿瘤细胞中的异位表达代表了肿瘤免疫逃避的潜在重要机制，并作为癌症免疫治疗的有希望的分子靶点。
Tumor immune escape is a major obstacle in cancer immunotherapy but the mechanisms involved remain poorly understood. We have previously developed an immune evasion tumor model using an in vivo immune selection strategy and revealed Akt-mediated immune resistance to anti-tumor immunity induced by various cancer immunotherapeutic agents. In the current study, we employed microarray gene analysis to identify an Akt-activating candidate molecule overexpressed in immune resistant tumors compared to parental tumors. X-linked lymphocyte-regulated protein pM1 (XLR) gene was the most upregulated in immune-resistant tumors compared to parental tumor cells. Furthermore, the retroviral transduction of XLR in parental tumor cells led to activation of Akt, resulting in upregulation of anti-apoptotic proteins and the induction of immune resistance phenotype in parental tumor cells. In addition, we found that transduction of parental tumor cells with other homologous genes from the mouse XLR family, such as synaptonemal complex protein 3 (SCP3) and XLR-related, meiosis regulated protein (XMR) and its human counterpart of SCP3 (hSCP3) also led to activation of Akt, resulting in the upregulation of anti-apoptotic proteins and induction of immune resistance phenotype. Importantly, characterization of a panel of human cervical cancers revealed relatively higher expression levels of hSCP3 in human cervical cancer tissue compared to normal cervical tissue. Thus, our data indicate that ectopic expression of XLR and its homologs in tumor cells represents a potentially important mechanism for tumor immune evasion and serves as a promising molecular target for cancer immunotherapy.