In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro
In vivo antitumor function of tumor antigen-specific CTLs generated in the presence of OX40 co-stimulation in vitro
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DOI：
10.1002/ijc.31244
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发表时间：
2018-06-01
影响因子：
6.4
通讯作者：
Tani, Masaji
中科院分区：
文献类型：
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作者：
Ngoc Pham Minh;Murata, Satoshi;Tani, Masaji
免疫细胞转移（ACT）是一种新兴的和有前途的癌症免疫疗法，已通过各种方法得到改进。在这里，我们描述了肿瘤Ag特异性效应CD 8（+）T细胞的独特特征和功能，与肿瘤特异性肽和刺激性抗OX 40抗体共培养，然后用于ACT治疗荷瘤小鼠受体。脾T细胞获自已注射表达HER 2/neu（neu）的肿瘤和neu疫苗的野生型FVB/N小鼠。然后，在存在或不存在激动性抗OX 40单克隆抗体的情况下，将细胞与源自neu的主要组织相容性复合物（MHC）I类肽在体外孵育7天，然后分离CD 8（+）T细胞用于ACT治疗。OX 40驱动的肿瘤Ag特异性效应CD 8（+）T细胞的体外增殖能力低于非OX 40驱动的肿瘤Ag特异性效应CD 8（+）T细胞，但它们表达显著更多的早期T细胞分化标志物，如CD 27、CD 62 L和CCR 7，以及显著更高水平的Bcl-2（一种抗凋亡蛋白）。这些OX 40驱动的肿瘤Ag特异性效应CD 8（+）T细胞，当转移到携带肿瘤的受体中时，表现出强大的增殖能力，并成功地根除了已建立的肿瘤。此外，这些细胞表现出长期的抗肿瘤功能，并且似乎被确立为记忆T细胞。我们的研究结果表明了一种可能的体外方法来提高ACT的疗效，这种方法简单，只需要少量的调节剂，并且可以潜在地避免与体内共刺激相关的几种毒性。OX 40共刺激通路是一种有前途的抗肿瘤免疫增强剂，但在I期临床试验中活化显示出轻度至中度毒性。在此，在用于过继细胞转移之前，效应CD 8 + T细胞与肿瘤肽和激动性0X 40抗体的体外共培养显著改善了小鼠模型中的肿瘤清除。OX 40驱动的肿瘤特异性效应CD 8 + T细胞提供了长期的抗肿瘤功能，而OX 40途径的离体活化预计会降低患者的毒性。
Adoptive cell transfer (ACT) is an emerging and promising cancer immunotherapy that has been improved through various approaches. Here, we described the distinctive characteristics and functions of tumor Ag-specific effector CD8(+) T-cells, co-cultured with a tumor-specific peptide and a stimulatory anti-OX40 antibody, before being used for ACT therapy in tumor-bearing mouse recipients. Splenic T-cells were obtained from wild-type FVB/N mice that had been injected with a HER2/neu (neu)-expressing tumor and a neu-vaccine. The cells were then incubated for 7 days in vitro with a major histocompatibility complex (MHC) class I peptide derived from neu, in the presence or absence of an agonistic anti-OX40 monoclonal antibody, before CD8(+) T cells were isolated for use in ACT therapy. The proliferative ability of OX40-driven tumor Ag-specific effector CD8(+) T-cells in vitro was less than that of non-OX40-driven tumor Ag-specific effector CD8(+) T-cells, but they expressed significantly more early T-cell differentiation markers, such as CD27, CD62L and CCR7, and significantly higher levels of Bcl-2, an anti-apoptotic protein. These OX40-driven tumor Ag-specific effector CD8(+) T-cells, when transferred into tumor-bearing recipients, demonstrated potent proliferation capability and successfully eradicated the established tumor. In addition, these cells exhibited long-term antitumor function, and appeared to be established as memory T-cells. Our findings suggest a possible in vitro approach for improving the efficacy of ACT, which is simple, requires only a small amount of modulator, and can potentially avoid several toxicities associated with co-stimulation in vivo.What's new? The OX40 co-stimulatory pathway is a promising enhancer of anti-tumor immunity but activation showed mild-to-moderate toxicity in a phase I clinical trial. Here, in vitro co-culture of effector CD8+ T-cells with a tumor peptide and an agonistic OX40 antibody prior to use in adoptive cell transfer markedly improved tumor clearance in a mouse model. The OX40-driven tumor-specific effector CD8+ T-cells provided long-term antitumor function while the ex vivo activation of OX40 pathway is expected to reduce toxicity in patients.