Identification of a Wilms' tumor1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes
Identification of a Wilms' tumor1-derived immunogenic CD4(+) T-cell epitope that is recognized in the context of common Caucasian HLA-DR haplotypes
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鉴定出维尔姆斯肿瘤 1 衍生的免疫原性 CD4( ) T 细胞表位，该表位在常见白种人 HLA-DR 单倍型的背景下被识别
作者：
Anguille S;Fujiki F;et al
Wilms ' tumor 1 （WT1）蛋白是一种肿瘤相关抗原，在多种实体和血液系统恶性肿瘤中过表达。已知WT1在急性髓性白血病（AML）中也经常过表达，因此适合用于AML的抗原靶向免疫治疗。先前的临床试验，包括肽和wt1靶向树突状细胞（DC）疫苗方法，已经为基于wt1的免疫疗法在AML患者中的临床抗白血病活性提供了切实的证据。一些特性使WT1成为AML的理想免疫治疗靶点，包括它在大量AML细胞和白血病干细胞室中的过表达，它在白血病发生中的作用以及它强大的免疫原性。事实上，WT1是为数不多的从不同CD4+辅助性t细胞表位中鉴定出的白血病相关抗原之一，这无疑有助于其优越的免疫原性，因为CD4+ t细胞辅助被认为是诱导有效抗肿瘤免疫的关键。在此背景下，我们之前已经确定了一种新的16元wt1衍生的CD4+辅助t细胞表位WT1332-347 (KRYFKLSHLQMHSRKH)，它具有高度混杂的人类白细胞抗原（HLA） II类结合能力。事实上，WT1332-347被证明可以识别各种HLA-DR和dp分子，包括HLA-DRB1* 04:05，-DRB1* 15:01,-DRB1* 15:02,-DPB1* 05:01（未发表的研究）和dpb1 * 09:01。9这些HLA等位基因在亚洲人中很常见，9但除了HLA- drb1 * 15:01外，在欧洲血统人群中相对罕见。10目前，WT1332-347是否可以与白种人中更常见的主要组织相容性复合体II类分子结合，以及该肽是否可以广泛应用于这些人群的免疫治疗，仍然是未知的。在本研究中，我们旨在研究WT1332-347是否可以由HLA-DRB1* 07:01表达，这是高加索人中最常见的HLA-DRB1等位基因之一，据报道频率高达30%。10,11为此，我们将HLA-DRB1* 07:01阳性的健康高加索人供者（DRB1* 07:01 / 12:01, DRB3* 02:02, DRB4* 01:03:01: 02N）外周血单个核细胞（PBMCs）在WT1332-347肽存在下培养，以启动CD4+ T细胞。1周后
The Wilms’ tumor 1 (WT1) protein is a tumor-associated antigen that is overexpressed in a wide range of solid and hematological malignancies. 1 WT1 is also known to be frequently overexpressed in acute myeloid leukemia (AML) and is thus suitable for antigentargeted immunotherapy of AML. 2 Previous clinical trials, including both peptide and WT1-targeted dendritic cell (DC) vaccine approaches, have already provided tangible evidence of the clinical anti-leukemic activity of WT1-based immunotherapy in AML patients. 1, 3–7 Several characteristics make WT1 an ideal immunotherapeutic target in AML, including its overexpression in bulk AML cells as well as in the leukemic stem cell compartment, its established role in leukemogenesis and its potent immunogenicity. 2 The fact that WT1 is one of the few leukemiaassociated antigens from which different CD4+ helper T-cell epitopes have been identified undoubtedly contributes to its superior immunogenicity profile, 2 as CD4+ T-cell help is considered critical for the induction of effective anti-tumor immunity. 8Within this context, we have previously identified a novel, 16-mer WT1-derived CD4+ helper T-cell epitope, WT1332–347 (KRYFKLSHLQMHSRKH), which possesses a highly promiscuous human leukocyte antigen (HLA) class II binding capacity. Indeed, WT1332–347 was shown to be recognized in the context of various HLA-DR and-DP molecules, including HLA-DRB1* 04: 05,-DRB1* 15: 01,-DRB1* 15: 02,-DPB1* 05: 01 (unpublished work) and-DPB1* 09: 01. 9 These HLA alleles are frequent among Asians, 9 but, with the exception of HLA-DRB1* 15: 01, are relatively rare in populations of European descent. 10 At the present time, it remains elusive whether WT1332–347 can bind to major histocompatibility complex class II molecules that are more common among Caucasians and, thus, whether this peptide could be broadly applicable for immunotherapy in those populations. In this study, we aimed to address whether WT1332–347 can be presented by HLA-DRB1* 07: 01, which is one of the most common HLA-DRB1 alleles among Caucasians with reported frequencies of up to 30%. 10, 11 To this end, peripheral blood mononuclear cells (PBMCs) of an HLA-DRB1* 07: 01-positive healthy Caucasian donor (DRB1* 07: 01/12: 01, DRB3* 02: 02, DRB4* 01: 03: 01: 02N) were cultured in the presence of WT1332–347 peptide in order to prime CD4+ T cells. After 1 week of