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ALK and RET Inhibitors Promote HLA Class I Antigen Presentation and Unmask New Antigens within the Tumor Immunopeptidome.
Cancer Immunology Research ( IF 10.1 ) Pub Date : 2019-09-20 , DOI: 10.1158/2326-6066.cir-19-0056
Claire Y Oh 1, 2 , Martin G Klatt 1 , Christopher Bourne 1, 2 , Tao Dao 1 , Megan M Dacek 1, 2 , Elliott J Brea 1, 2 , Sung Soo Mun 1 , Aaron Y Chang 1, 2 , Tatyana Korontsvit 1 , David A Scheinberg 1, 2
Affiliation  

T-cell immunotherapies are often thwarted by the limited presentation of tumor-specific antigens abetted by the downregulation of human leukocyte antigen (HLA). We showed that drugs inhibiting ALK and RET produced dose-related increases in cell-surface HLA in tumor cells bearing these mutated kinases in vitro and in vivo, as well as elevated transcript and protein expression of HLA and other antigen-processing machinery. Subsequent analysis of HLA-presented peptides after ALK and RET inhibitor treatment identified large changes in the immunopeptidome with the appearance of hundreds of new antigens, including T-cell epitopes associated with impaired peptide processing (TEIPP) peptides. ALK inhibition additionally decreased PD-L1 levels by 75%. Therefore, these oncogenes may enhance cancer formation by allowing tumors to evade the immune system by downregulating HLA expression. Altogether, RET and ALK inhibitors could enhance T-cell-based immunotherapies by upregulating HLA, decreasing checkpoint blockade ligands, and revealing new, immunogenic, cancer-associated antigens.

中文翻译:

ALK 和 RET 抑制剂促进 HLA I 类抗原呈递并揭示肿瘤免疫肽组内的新抗原。

T 细胞免疫疗法通常因人类白细胞抗原 (HLA) 下调所助长的肿瘤特异性抗原的有限呈递而受阻。我们表明,抑制 ALK 和 RET 的药物在体外和体内产生了带有这些突变激酶的肿瘤细胞中细胞表面 HLA 的剂量相关增加,以及 HLA 和其他抗原加工机制的转录和蛋白质表达升高。随后对 ALK 和 RET 抑制剂处理后 HLA 呈递肽的分析发现免疫肽组发生了巨大变化,出现了数百种新抗原,包括与肽加工受损 (TEIPP) 肽相关的 T 细胞表位。ALK 抑制还可将 PD-L1 水平降低 75%。所以,这些致癌基因可能通过下调 HLA 表达使肿瘤逃避免疫系统而促进癌症形成。总之,RET 和 ALK 抑制剂可以通过上调 HLA、减少检查点阻断配体和揭示新的免疫原性癌症相关抗原来增强基于 T 细胞的免疫疗法。
更新日期:2019-12-02
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