T cells specific for a TAP-independent self-peptide remain naïve in tumor-bearing mice and are fully exploitable for therapy.
T cells specific for a TAP-independent self-peptide remain naïve in tumor-bearing mice and are fully exploitable for therapy.
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DOI：
10.1080/2162402x.2017.1382793
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
van Hall T
中科院分区：
文献类型：
--
作者：
Doorduijn EM;Sluijter M;Marijt KA;Querido BJ;van der Burg SH;van Hall T
癌症通常通过降低其细胞表面上的肽：MHC-I复合物来逃避免疫识别。由于TAP缺陷导致的有限肽供应导致此类MHC-Ilow免疫逃逸变体。在此之前，我们报道了一类TAP独立的自身肽，称为TEIPP，具有这些肿瘤的选择性呈递。在这里，我们证明了与对常规肿瘤抗原特异性的T细胞相反，TEIPP导向的T细胞在携带免疫逃逸肿瘤的小鼠中仍然是幼稚的。这种未受影响的状态是由肿瘤上低水平的MHC-I和宿主APC未能交叉呈递低水平的抗原蛋白引起的。重要的是，MHC-I、抗原或共刺激水平的增加导致TEIPP特异性T细胞通过直接呈递的有效活化。通过CRISPR/Cas9技术对肿瘤细胞中相关MHC-I等位基因的遗传敲低确实消除了T细胞活化。疫苗介导的TEIPP特异性T细胞的引发诱导有效归巢至MHC-Ilow肿瘤，随后保护小鼠免于其MHC-Ilow肿瘤的生长。因此，我们的数据开启了在癌症患者中寻找TEIPP特异性T细胞以探索其针对MHC-Ilow肿瘤细胞的应用。
Cancers frequently evade immune-recognition by lowering peptide:MHC-I complexes on their cell surface. Limited peptide supply due to TAP-deficiency results in such MHC-Ilow immune-escape variants. Previously, we reported on a category of TAP-independent self-peptides, called TEIPP, with selective presentation by these tumors. Here we demonstrate that in contrast to T cells specific for conventional tumor antigens, TEIPP-directed T cells remain naïve in mice bearing immune-escaped tumors. This unaffected state was caused by low levels of MHC-I on the tumors and the failure to cross-present low levels of antigenic protein by host APCs. Importantly, increased levels of MHC-I, antigen or co-stimulation resulted in potent activation of TEIPP-specific T cells via direct presentation. Genetic knockdown by CRISPR/Cas9 technology of the relevant MHC-I allele in tumor cells indeed abrogated T cell activation. Vaccine-mediated priming of TEIPP-specific T cells induced efficient homing to MHC-Ilow tumors and subsequently protected mice against outgrowth of their MHC-Ilow tumor. Thus, our data open up the search of TEIPP-specific T cells in cancer patients to explore their application against MHC-Ilow tumor cells.