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ER-aminopeptidase 1 determines the processing and presentation of an immunotherapy-relevant melanoma epitope.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2019-11-27 , DOI: 10.1002/eji.201948116 Kathrin Textoris-Taube 1 , Clemens Cammann 2 , Petra Henklein 3 , Eylin Topfstedt 2 , Frédéric Ebstein 3 , Sarah Henze 4 , Juliane Liepe 4 , Fang Zhao 5 , Dirk Schadendorf 5 , Burkhardt Dahlmann 3 , Wolfgang Uckert 6 , Annette Paschen 5 , Michele Mishto 7, 8 , Ulrike Seifert 2
European Journal of Immunology ( IF 4.5 ) Pub Date : 2019-11-27 , DOI: 10.1002/eji.201948116 Kathrin Textoris-Taube 1 , Clemens Cammann 2 , Petra Henklein 3 , Eylin Topfstedt 2 , Frédéric Ebstein 3 , Sarah Henze 4 , Juliane Liepe 4 , Fang Zhao 5 , Dirk Schadendorf 5 , Burkhardt Dahlmann 3 , Wolfgang Uckert 6 , Annette Paschen 5 , Michele Mishto 7, 8 , Ulrike Seifert 2
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Dissecting the different steps of the processing and presentation of tumor-associated antigens is a key aspect of immunotherapies enabling to tackle the immune response evasion attempts of cancer cells. The immunodominant glycoprotein gp100209-217 epitope, which is liberated from the melanoma differentiation antigen gp100PMEL17 , is part of immunotherapy trials. By analyzing different human melanoma cell lines, we here demonstrate that a pool of N-terminal extended peptides sharing the common minimal epitope is generated by melanoma proteasome subtypes. In vitro and in cellulo experiments indicate that ER-resident aminopeptidase 1 (ERAP1)-but not ERAP2-defines the processing of this peptide pool thereby modulating the T-cell recognition of melanoma cells. By combining the outcomes of our studies and others, we can sketch the complex processing and endogenous presentation pathway of the gp100209-217 -containing epitope/peptides, which are produced by proteasomes and are translocated to the vesicular compartment through different pathways, where the precursor peptides that reach the endoplasmic reticulum are further processed by ERAP1. The latter step enhances the activation of epitope-specific T lymphocytes, which might be a target to improve the efficiency of anti-melanoma immunotherapy.
中文翻译：
ER-氨基肽酶1决定了与免疫疗法相关的黑色素瘤抗原决定簇的加工和呈递。
剖析与肿瘤相关的抗原的加工和呈递的不同步骤是免疫疗法的关键方面，能够解决癌细胞的免疫应答逃避尝试。从黑色素瘤分化抗原gp100PMEL17中释放出来的免疫显性糖蛋白gp100209-217表位是免疫疗法试验的一部分。通过分析不同的人类黑素瘤细胞系，我们在这里证明了由黑素瘤蛋白酶体亚型产生的共有共同最小表位的N末端延伸肽库。体外和纤维素实验表明，驻留ER的氨肽酶1（ERAP1）而不是ERAP2定义了该肽库的加工过程，从而调节了黑色素瘤细胞的T细胞识别能力。通过结合我们的研究成果和其他研究成果，我们可以勾勒出含gp100209-217的表位/肽的复杂加工和内源性呈递途径，它们由蛋白酶体产生，并通过不同的途径转移到囊泡区，其中到达内质网的前体肽被进一步加工， ERAP1。后面的步骤增强了表位特异性T淋巴细胞的激活，这可能是提高抗黑素瘤免疫疗法效率的目标。
更新日期：2019-11-28
中文翻译：
ER-氨基肽酶1决定了与免疫疗法相关的黑色素瘤抗原决定簇的加工和呈递。
剖析与肿瘤相关的抗原的加工和呈递的不同步骤是免疫疗法的关键方面，能够解决癌细胞的免疫应答逃避尝试。从黑色素瘤分化抗原gp100PMEL17中释放出来的免疫显性糖蛋白gp100209-217表位是免疫疗法试验的一部分。通过分析不同的人类黑素瘤细胞系，我们在这里证明了由黑素瘤蛋白酶体亚型产生的共有共同最小表位的N末端延伸肽库。体外和纤维素实验表明，驻留ER的氨肽酶1（ERAP1）而不是ERAP2定义了该肽库的加工过程，从而调节了黑色素瘤细胞的T细胞识别能力。通过结合我们的研究成果和其他研究成果，我们可以勾勒出含gp100209-217的表位/肽的复杂加工和内源性呈递途径，它们由蛋白酶体产生，并通过不同的途径转移到囊泡区，其中到达内质网的前体肽被进一步加工， ERAP1。后面的步骤增强了表位特异性T淋巴细胞的激活，这可能是提高抗黑素瘤免疫疗法效率的目标。
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