Molecular mechanism of MART-1+/A*0201+ human melanoma resistance to specific CTL-killing despite functional tumor-CTL interaction.
Molecular mechanism of MART-1+/A*0201+ human melanoma resistance to specific CTL-killing despite functional tumor-CTL interaction.
复制标题
DOI：
10.1158/0008-5472.can-10-1296
复制
发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Economou JS
中科院分区：
文献类型：
--
作者：
Jazirehi AR;Baritaki S;Koya RC;Bonavida B;Economou JS
转移性黑色素瘤患者的持久反应通常仍难以实现。用表达针对黑色素瘤抗原MART-127-35/HLAA*0201(由F5细胞毒性T淋巴细胞[F5 CTL]识别)的高亲和力T细胞受体α/β的体外工程淋巴细胞过继细胞治疗已被发现对某些患者有益。然而，许多其他患者天生反应迟钝和/或复发，原因不明。为了分析获得性抗性的基础和逆转它的策略，我们在选择性F5 CTL压力下，从相对敏感的亲本系中建立了F5 CTL抗性(R)人黑色素瘤克隆。这些克隆的表面MART-127-35/HLA-A*0201没有改变，F5 CTL识别和相互作用类似于亲本系。然而，R克隆对F5CTL杀伤具有抵抗力，表现出NF-κB生存通路的高度激活，以及抗凋亡基因Bcl2、Bclxl和Mcl-1的过度表达。药物抑制NF-κB通路、Bcl2家族成员或蛋白酶体可增加对F5CTL杀伤的敏感性，后者可降低NF-κB的活性，减少抗凋亡基因的表达。特异的基因沉默(通过siRNA)通过逆转R克隆抗性证实了抗凋亡因子的保护作用。综上所述，我们的研究结果表明，长期免疫治疗可能会对耐药细胞的发展施加选择，这些细胞对高度亲和的和特定的黑色素瘤反应性CTL没有反应，尽管由于抗凋亡信号通路的激活而保持了功能性多肽：MHC复合体的表达。虽然对CTL没有反应，但我们的结果认为，耐药细胞可以通过联合应用靶向抑制剂来对抗细胞凋亡的生存途径而对免疫治疗重新敏感。
Durable responses in metastatic melanoma patients remain generally difficult to achieve. Adoptive cell therapy with ex vivo engineered lymphocytes expressing high affinity T cell receptors TCRα/β for the melanoma antigen MART-127-35/HLA A*0201 (recognized by F5 cytotoxic T lymphocytes [F5 CTLs]) has been found to benefit certain patients. However, many other patients are inherently unresponsive and/or relapse for unknown reasons. To analyze the basis for the acquired-resistance and strategies to reverse it, we established F5 CTLresistant (R) human melanoma clones from relatively sensitive parental lines under selective F5 CTL pressure. Surface MART-127-35/HLA-A*0201 in these clones was unaltered and F5 CTLs recognized and interacted with them similarly to the parental lines. Nevertheless, the R clones were resistant to F5 CTL killing, exhibited hyperactivation of the NF-κB survival pathway, and overexpression of the anti-apoptotic genes Bcl-2, Bcl-xL and Mcl-1. Sensitivity to F5 CTL-killing could be increased by pharmacological inhibition of the NF-κB pathway, Bcl-2 family members, or the proteasome, the latter of which reduced NF-κB activity and diminished anti-apoptotic gene expression. Specific gene-silencing (by siRNA) confirmed the protective role of anti-apoptotic factors by reversing R clone resistance. Together, our findings suggest that long-term immunotherapy may impose a selection for the development of resistant cells that are unresponsive to highly avid and specific melanoma-reactive CTLs, despite maintaining expression of functional peptide:MHC complexes, due to activation of anti-apoptotic signaling pathways. Though unresponsive to CTL, our results argue that resistant cells can be re-sensitized to immunotherapy with co-administration of targeted inhibitors to anti-apoptotic survival pathways.