A Nanobody Against Cytotoxic T-Lymphocyte Associated Antigen-4 Increases the Anti-Tumor Effects of Specific CD8(+) T Cells.
A Nanobody Against Cytotoxic T-Lymphocyte Associated Antigen-4 Increases the Anti-Tumor Effects of Specific CD8(+) T Cells.
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CTLA-4 纳米抗体可增强特定 CD8 T 细胞的抗肿瘤作用
DOI：
10.1166/jbn.2019.2859
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发表时间：
2019-11-01
影响因子：
2.9
通讯作者：
中科院分区：
文献类型：
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作者：
基于免疫细胞的免疫疗法通常利用细胞毒性T淋巴细胞（CTL），离体扩增这些细胞。这种扩增传统上通过使用能够与T细胞相互作用的自体APC来实现。然而，诸如CTLA-4途径的偶然抑制程序可损害T细胞增殖。因此，我们设计了一种对CTLA-4（CTLA-4 Nb 16）具有特异性的纳米抗体，然后我们使用这种分子来评估其破坏CTLA-4信号传导的能力，从而克服T细胞的负共刺激。在CTLA-4 Nb 16刺激下，树突状细胞/肝癌融合细胞（DC/HepG 2-FC）在体外增强了自体CD 8 + T细胞的增殖和IFN-γ的产生，从而导致增强的肿瘤细胞杀伤。在过继性CD 8+免疫治疗的背景下使用这种方法导致对鼠NOD/SCID肝癌或乳腺癌异种移植模型中的肿瘤生长的显著抑制。我们还观察到肿瘤细胞凋亡显著增加，小鼠存活率相应增加。因此，这些发现表明，响应于纳米抗体刺激，DC/肿瘤细胞-FC诱导的特异性CTL表现出上级抗肿瘤功效，使其成为在癌症患者中实现更好的过继免疫治疗结果的潜在有价值的手段。
Adoptive cell-based immunotherapy typically utilizes cytotoxic T lymphocytes (CTLs), expanding these cells ex vivo. Such expansion is traditionally accomplished through the use of autologous APCs that are capable of interactions with T cells. However, incidental inhibitory program such as CTLA-4 pathway can impair T cell proliferation. We therefore designed a nanobody which is specific for CTLA-4 (CTLA-4 Nb 16), and we then used this molecule to assess its ability to disrupt CTLA-4 signaling and thereby overcome negative costimulation of T cells. With CTLA-4 Nb16 stimulation, dendritic cell/hepatocellular carcinoma fusion cells (DC/HepG2-FCs) enhanced autologous CD8+ T cell proliferation and production of IFN-γ in vitro, thereby leading to enhanced killing of tumor cells. Using this approach in the context of adoptive CD8+ immunotherapy led to a marked suppression of tumor growth in murine NOD/SCID hepatocarcinoma or breast cancer xenograft models. We also observed significantly increased tumor cell apoptosis, and corresponding increases in murine survival. These findings thus demonstrate that in response to nanobody stimulation, DC/tumor cells-FC-induced specific CTLs exhibit superior anti-tumor efficacy, making this a potentially valuable means of achieving better adoptive immunotherapy outcomes in cancer patients.
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DOI：
10.1002/iid3.99
发表时间：
2016-03
期刊：
Immunity, inflammation and disease
影响因子：
--
作者：
Atomura R;Sanui T;Fukuda T;Tanaka U;Toyoda K;Taketomi T;Yamamichi K;Akiyama H;Nishimura F
通讯作者：
Nishimura F
影响因子：
3.6
作者：
El Ansary M;Mogawer S;Elhamid SA;Alwakil S;Aboelkasem F;Sabaawy HE;Abdelhalim O
通讯作者：
Abdelhalim O
影响因子：
--
作者：
Liedtke C;Kolberg HC
通讯作者：
Kolberg HC
影响因子：
11.5
作者：
Butterfield, LH;Ribas, A;Economou, JS
通讯作者：
Economou, JS
影响因子：
17.1
作者：
Iwama, Shintaro;De Remigis, Alessandra;Caturegli, Patrizio
通讯作者：
Caturegli, Patrizio