Dao Tao, Korontsvit Tatyana, Zakhaleva Victoria, Jarvis Casey, Mondello Patrizia, Oh Claire, Scheinberg David A
Molecular Pharmacology Program, Sloan Kettering Institute , New York, NY, USA.
Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, NY, USA.
Oncoimmunology. 2016 Dec 7;6(2):e1252895. doi: 10.1080/2162402X.2016.1252895. eCollection 2017.
The Wilms' tumor oncogene protein (WT1) is a highly validated tumor antigen for immunotherapy. WT1-targeted immunotherapy has been extensively explored in multiple human trials in various cancers. However, clinical investigations using WT1 epitopes have generally focused on two peptides, HLA-restricted to HLA-A02:01 or HLA-A24:02. The goal of this study was to identify new epitopes derived from WT1, to expand the potential use of WT1 as a target of immunotherapy. Using computer-based MHC-binding algorithms and validation of the T cell responses specific for the identified peptides, we found that a recently identified HLA-A24:02-binding epitope (239-247), NQMNLGATL (NQM), was also a strong CD8 T cell epitope for HLA-A02:01 molecule. A peptide second position Q240L substitution (NLM) or Q240Y substitution (NYM), further enhanced the T cell responses in both HLA-A02:01 positive and HLA-A24:02 positive healthy donors. Importantly, T cells stimulated with the new analog peptides displayed heteroclitic cross-reactivity with the native NQM sequence and were able to kill HLA-matched WT1-positive tumor cell lines and primary leukemia blasts. In addition, longer native and heteroclitic HLA-DR.B1-binding peptides, comprising the nine amino acid NQM or NLM sequences, could induce T cell response that recognized the CD8 epitope NQM, suggesting the processing and the presentation by HLA-A02:01 molecules of the CD8 T cell epitope embedded within it. Our studies suggest that the analog peptides NLM and NYM could be potential candidates for future immunotherapy targeting WT1 positive cancers in the context of HLA-A02:01 and A*24:02 positive populations.
肾母细胞瘤致癌基因蛋白（WT1）是一种经过高度验证的免疫治疗肿瘤抗原。针对WT1的免疫疗法已在多种癌症的多项人体试验中得到广泛探索。然而，使用WT1表位的临床研究通常集中在两种肽上，它们受限于HLA-A02:01或HLA-A24:02的HLA限制。本研究的目的是鉴定源自WT1的新表位，以扩大WT1作为免疫治疗靶点的潜在用途。通过基于计算机的MHC结合算法以及对鉴定出的肽特异性T细胞反应的验证，我们发现最近鉴定出的一种HLA-A24:02结合表位（239-247），NQMNLGATL（NQM），也是HLA-A02:01分子的强CD8 T细胞表位。肽的第二位Q240L替换（NLM）或Q240Y替换（NYM），进一步增强了HLA-A02:01阳性和HLA-A24:02阳性健康供体中的T细胞反应。重要的是，用新的类似物肽刺激的T细胞与天然NQM序列表现出异源交叉反应，并且能够杀死HLA匹配的WT1阳性肿瘤细胞系和原发性白血病母细胞。此外，包含九个氨基酸NQM或NLM序列的更长的天然和异源HLA-DR.B1结合肽，可以诱导识别CD8表位NQM的T细胞反应，这表明其中嵌入的CD8 T细胞表位可由HLA-A02:01分子进行加工和呈递。我们的研究表明，类似物肽NLM和NYM可能是未来针对HLA-A02:01和A*24:02阳性人群中WT1阳性癌症进行免疫治疗的潜在候选物。
