INSERM UMR 1186, Integrative Tumour Immunology and Genetic Oncology, Gustave Roussy, EPHE, PSL, Fac. de Médecine, Univ. Paris-Sud, Université Paris-Saclay, 94805, Villejuif, France.
ElyssaMed, Paris Biotech Santé, 75014, Paris, France.
Nat Commun. 2018 Nov 30;9(1):5097. doi: 10.1038/s41467-018-07603-1.
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) 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 mice adoptively transferred with human PBMC. Thus, ppCT-specific T lymphocytes are promising effectors for treatment of tumours that have escaped immune recognition.
肿瘤通常通过下调 TAP 来逃避 CD8 T 细胞免疫。与受损肽加工相关的 T 细胞表位是免疫原性的非突变新抗原，在肿瘤免疫逃逸期间出现。前降钙素 (ppCT) 新抗原属于此类抗原。在这里，我们表明大多数人类肺肿瘤显示 TAP 的改变表达并且经常表达 ppCT 自身抗原。我们还表明，ppCT 包括由 TAP 非依赖性和依赖性途径加工的 HLA-A2 限制性表位。加工发生在内质网中，通过信号肽酶和信号肽肽酶，或者在信号肽前体释放或钙蛋白酶底物的逆向转运通过内质网相关降解后在细胞质中发生。值得注意的是，基于 ppCT 肽的免疫疗法诱导针对抗原加工和呈递机制受损的肿瘤的有效 T 细胞反应，这些肿瘤被移植到 HLA-A*0201 转基因小鼠中，并在接受人 PBMC 的 NOD-scid-Il2rγ 小鼠中进行过继转移。因此，ppCT 特异性 T 淋巴细胞是治疗逃避免疫识别的肿瘤的有前途的效应物。
