de Waard Antonius A, Verkerk Tamara, Hoefakker Kelly, van der Steen Dirk M, Jongsma Marlieke L M, Melamed Kadosh Dganit, Bliss Sophie, de Ru Arnoud H, Admon Arie, van Veelen Peter A, Griffioen Marieke, Heemskerk Mirjam H M, Spaapen Robbert M
Department of Immunopathology, Sanquin Research, Amsterdam, CX 1066, The Netherlands.
Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, CX 1066, The Netherlands.
iScience. 2021 Jan 9;24(2):102051. doi: 10.1016/j.isci.2021.102051. eCollection 2021 Feb 19.
Tumors with an impaired transporter associated with antigen processing (TAP) present several endoplasmic reticulum-derived self-antigens on HLA class I (HLA-I) which are absent on healthy cells. Selection of such TAP-independent antigens for T cell-based immunotherapy should include analysis of their expression on healthy cells to prevent therapy-induced adverse toxicities. However, it is unknown how the absence of clinically relevant antigens on healthy cells needs to be validated. Here, we monitored TAP-independent antigen presentation on various healthy cells after establishing a T cell tool recognizing a TAP-independent signal sequence receptor 1-derived antigen. We found that most but not all healthy cells present this antigen under normal and inflammatory conditions, indicating that TAP-independent antigen presentation is a variable phenomenon. Our data emphasize the necessity of extensive testing of a wide variety of healthy cell types to define clinically relevant TAP-independent antigens that can be safely targeted by immunotherapy.
与抗原加工相关的转运体（TAP）受损的肿瘤在HLA I类（HLA-I）上呈现几种内质网衍生的自身抗原，而这些抗原在健康细胞上不存在。为基于T细胞的免疫疗法选择此类不依赖TAP的抗原应包括分析它们在健康细胞上的表达，以防止治疗引起的不良毒性。然而，尚不清楚如何验证健康细胞上缺乏临床相关抗原。在此，我们建立了一种识别不依赖TAP的信号序列受体1衍生抗原的T细胞工具，之后监测了各种健康细胞上不依赖TAP的抗原呈递情况。我们发现，大多数但并非所有健康细胞在正常和炎症条件下都呈递这种抗原，这表明不依赖TAP的抗原呈递是一种可变现象。我们的数据强调了对多种健康细胞类型进行广泛测试的必要性，以确定可通过免疫疗法安全靶向的临床相关不依赖TAP的抗原。
