GRIK2 is a target for bladder cancer stem-like cell-targeting immunotherapy
GRIK2 is a target for bladder cancer stem-like cell-targeting immunotherapy
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DOI：
10.1007/s00262-021-03025-z
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发表时间：
2021-08-18
影响因子：
5.8
通讯作者：
Torigoe, Toshihiko
中科院分区：
文献类型：
--
作者：
Miyata, Haruka;Hirohashi, Yoshihiko;Torigoe, Toshihiko
最近的研究表明，耐药的肿瘤干细胞(CSCs)/肿瘤起始细胞(CICs)可以被细胞毒性T淋巴细胞(CTL)靶向。CTL识别来源于肿瘤相关抗原的抗原肽，因此，鉴定CSCs/CICs表达的肿瘤相关抗原是至关重要的。人类白细胞抗原(人类白细胞抗原)配基的质谱学分析可以分析自然表达的抗原肽，然而，人类白细胞抗原配基分析需要大量的细胞，对CSCs/CICs具有挑战性。在这项研究中，我们利用ALDEFLUOR方法建立了一种新的膀胱CSC/CIC模型，该模型来源于膀胱癌UM-UC-3细胞。将CSCs/CICs分离为乙醛脱氢酶(ALDH)高表达细胞，并建立了多个ALDH高表达克隆细胞。用CSCs/CICs对免疫缺陷小鼠的ALDH(高)克隆细胞进行球体形成和致瘤性实验。用ALDH(High)克隆细胞进行的HL A配基分析和基因表达的帽分析表明，在膀胱CSCs/CICs中有一个独特的抗原肽库，我们发现CSCs/CICs特异地表达了一种谷氨酸受体亲离子海人藻酸酶2(GRIK2)衍生的抗原肽(LMYDAVHVV)。GRIK2多肽特异性CTL克隆可识别GRIK2高表达的UM-UC-3细胞和ALDH(高)克隆细胞，提示GRIK2多肽可作为膀胱CSC/CIC靶向免疫治疗的新靶点。
Recent studies have revealed that treatment-resistant cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) can be targeted by cytotoxic T lymphocytes (CTLs). CTLs recognize antigenic peptides derived from tumor-associated antigens; thus, the identification of tumor-associated antigens expressed by CSCs/CICs is essential. Human leucocyte antigen (HLA) ligandome analysis using mass spectrometry enables the analysis of naturally expressed antigenic peptides; however, HLA ligandome analysis requires a large number of cells and is challenging for CSCs/CICs. In this study, we established a novel bladder CSC/CIC model from a bladder cancer cell line (UM-UC-3 cells) using an ALDEFLUOR assay. CSCs/CICs were isolated as aldehyde dehydrogenase (ALDH)-high cells and several ALDH(high) clone cells were established. ALDH(high) clone cells were enriched with CSCs/CICs by sphere formation and tumorigenicity in immunodeficient mice. HLA ligandome analysis and cap analysis of gene expression using ALDH(high) clone cells revealed a distinctive antigenic peptide repertoire in bladder CSCs/CICs, and we found that a glutamate receptor, ionotropic, kainite 2 (GRIK2)-derived antigenic peptide (LMYDAVHVV) was specifically expressed by CSCs/CICs. A GRIK2 peptide-specific CTL clone recognized GRIK2-overexpressing UM-UC-3 cells and ALDH(high) clone cells, indicating that GRIK2 peptide can be a novel target for bladder CSC/CIC-targeting immunotherapy.