ALK and RET Inhibitors Promote HLA Class I Antigen Presentation and Unmask New Antigens within the Tumor Immunopeptidome
ALK and RET Inhibitors Promote HLA Class I Antigen Presentation and Unmask New Antigens within the Tumor Immunopeptidome
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DOI：
10.1158/2326-6066.cir-19-0056
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发表时间：
2019-12-01
影响因子：
10.1
通讯作者：
Scheinberg, David A.
中科院分区：
文献类型：
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作者：
Oh, Claire Y.;Klatt, Martin G.;Scheinberg, David A.
T细胞免疫疗法经常受到肿瘤特异性抗原的有限呈递的阻碍，该肿瘤特异性抗原由人类白细胞抗原（HLA）的下调引起。我们发现，抑制ALK和RET的药物在体外和体内使携带这些突变激酶的肿瘤细胞中细胞表面HLA产生剂量相关的增加，以及HLA和其他抗原加工机制的转录和蛋白表达升高。ALK和RET抑制剂治疗后HLA呈递肽的后续分析发现免疫肽组发生了巨大变化，出现了数百种新抗原，包括与受损肽加工（TEIPP）肽相关的T细胞表位。ALK抑制还使PD-L1水平降低75%。因此，这些癌基因可能通过下调HLA表达使肿瘤逃避免疫系统而增强癌症形成。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。
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.