Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Clin Cancer Res. 2018 Jul 15;24(14):3366-3376. doi: 10.1158/1078-0432.CCR-17-2483. Epub 2018 Mar 1.
Cancer immunotherapy has shown promising clinical outcomes in many patients. However, some patients still fail to respond, and new strategies are needed to overcome resistance. The purpose of this study was to identify novel genes and understand the mechanisms that confer resistance to cancer immunotherapy. To identify genes mediating resistance to T-cell killing, we performed an open reading frame (ORF) screen of a kinome library to study whether overexpression of a gene in patient-derived melanoma cells could inhibit their susceptibility to killing by autologous tumor-infiltrating lymphocytes (TIL). The RNA-binding protein MEX3B was identified as a top candidate that decreased the susceptibility of melanoma cells to killing by TILs. Further analyses of anti-PD-1-treated melanoma patient tumor samples suggested that higher expression is associated with resistance to PD-1 blockade. In addition, significantly decreased levels of IFNγ were secreted from TILs incubated with MEX3B-overexpressing tumor cells. Interestingly, this phenotype was rescued upon overexpression of exogenous HLA-A2. Consistent with this, we observed decreased HLA-A expression in MEX3B-overexpressing tumor cells. Finally, luciferase reporter assays and RNA-binding protein immunoprecipitation assays suggest that this is due to MEX3B binding to the 3' untranslated region (UTR) of to destabilize the mRNA. MEX3B mediates resistance to cancer immunotherapy by binding to the 3' UTR of to destabilize the mRNA and thus downregulate HLA-A expression on the surface of tumor cells, thereby making the tumor cells unable to be recognized and killed by T cells. .
癌症免疫疗法在许多患者中显示出了有前景的临床结果。然而，一些患者仍然没有反应，需要新的策略来克服耐药性。本研究旨在鉴定新的基因，并了解赋予癌症免疫疗法耐药性的机制。为了鉴定介导 T 细胞杀伤耐药性的基因，我们对激酶文库进行了开放阅读框（ORF）筛选，以研究患者来源的黑色素瘤细胞中基因的过表达是否可以抑制其对自体肿瘤浸润淋巴细胞（TIL）杀伤的敏感性。RNA 结合蛋白 MEX3B 被鉴定为抑制 TIL 杀伤黑色素瘤细胞敏感性的顶级候选基因。对接受抗 PD-1 治疗的黑色素瘤患者肿瘤样本的进一步分析表明，较高的表达与对 PD-1 阻断的耐药性相关。此外，与表达 MEX3B 的肿瘤细胞孵育的 TIL 分泌的 IFNγ 显著减少。有趣的是，在外源 HLA-A2 过表达时，这种表型得到挽救。与此一致，我们观察到表达 MEX3B 的肿瘤细胞中 HLA-A 的表达减少。最后，荧光素酶报告基因测定和 RNA 结合蛋白免疫沉淀测定表明，这是由于 MEX3B 结合到 3'非翻译区（UTR），从而使 mRNA 不稳定。MEX3B 通过与 3'UTR 结合来破坏 的 mRNA 稳定性，从而下调肿瘤细胞表面 HLA-A 的表达，从而使肿瘤细胞无法被 T 细胞识别和杀伤，从而介导癌症免疫疗法的耐药性。
