Tumours often evade CD8 T-cell immunity by downregulating TAP. T-cell epitopes associated with impaired peptide processing are immunogenic non-mutated neoantigens that emerge during tumour immune evasion. The preprocalcitonin (ppCT)_16-25 neoepitope belongs to this category of antigens. Here we show that most human lung tumours display altered expression of TAP and frequently express ppCT self-antigen. We also show that ppCT includes HLA-A2-restricted epitopes that are processed by TAP-independent and -dependent pathways. Processing occurs in either the endoplasmic reticulum, by signal peptidase and signal peptide peptidase, or in the cytosol after release of a signal peptide precursor or retrotranslocation of a procalcitonin substrate by endoplasmic-reticulum-associated degradation. Remarkably, ppCT peptide-based immunotherapy induces efficient T-cell responses toward antigen processing and presenting machinery-impaired tumours transplanted into HLA-A*0201-transgenic mice and in NOD-scid-Il2rγ^null mice adoptively transferred with human PBMC. Thus, ppCT-specific T lymphocytes are promising effectors for treatment of tumours that have escaped immune recognition.

中文翻译：

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人降钙素原自身抗原产生TAP依赖性和非依赖性抗原决定簇，触发针对免疫逃逸的肿瘤的优化T细胞反应。

肿瘤通常通过下调TAP来逃避CD8 T细胞免疫。与肽加工受损有关的T细胞表位是免疫原性非突变的新抗原，在肿瘤免疫逃逸过程中出现。降钙素原（ppCT）_16-25新表位属于这一类抗原。在这里，我们显示大多数人类肺部肿瘤显示TAP的表达改变，并经常表达ppCT自身抗原。我们还显示ppCT包括HLA-A2限制性抗原决定簇，这些抗原决定簇是通过TAP依赖性和依赖性途径处理的。通过信号肽酶和信号肽肽酶在内质网中进行加工，或者在释放信号肽前体或降钙素原底物通过内质网相关降解而逆转后，在细胞质中进行加工。值得注意的是，PPCT基于肽的免疫治疗诱导朝向抗原加工有效的T细胞应答和呈现机械受损的肿瘤移植到HLA-A * 0201转基因小鼠和在NOD-SCID-Il2rγ^空与人PBMC过继转移的小鼠。因此，ppCT特异性T淋巴细胞是用于治疗逃避免疫识别的肿瘤的有希望的效应子。