Radiation-Induced Modulation of Costimulatory and Coinhibitory T-Cell Signaling Molecules on Human Prostate Carcinoma Cells Promotes Productive Antitumor Immune Interactions
Radiation-Induced Modulation of Costimulatory and Coinhibitory T-Cell Signaling Molecules on Human Prostate Carcinoma Cells Promotes Productive Antitumor Immune Interactions
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DOI：
10.1089/cbr.2013.1578
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发表时间：
2014-05-01
影响因子：
3.4
通讯作者：
Guha, Chandan
中科院分区：
文献类型：
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作者：
Bernstein, Michael B.;Garnett, Charlie T.;Guha, Chandan
我们试图确定单剂量外照射放射治疗 (EBRT) 是否可以在体外调节人前列腺癌 (PCa) 细胞系中 T 细胞共刺激和共抑制分子的表达特征。我们研究了经过调节的共刺激曲线的辐照 PCa 细胞对应答 T 细胞活性的功能影响。我们使用了三种 PCa 细胞系（DU145、PC3 和 LNCaP）和两种来自非癌性前列腺和肺组织的上皮细胞系。 EBRT 72小时后，通过流式细胞术评估四种免疫刺激分子（CD70、CD275/ICOSL、CD134L/OX40L和CD137L/41BBL）和两种免疫抑制标记物（CTLA-4/CD152和PD-L1/CD274）的表面表达。我们评估了几种辐射剂量的影响和调节表达的寿命。我们研究了细胞毒性 T 细胞 (CTL) 细胞毒性和 ELISPOT 测定对干扰素-γ (IFN-γ) 产生的辐射诱导调节癌细胞的功能影响。最后，我们评估了 EBRT 是否可以逆转 IFN-γ 诱导的 PD-L1 表达。 10 Gy EBRT 后，所有三种 PCa 细胞系中 OX40L 和 41BBL 的表达均增加； PC3细胞中CD70和ICOSL的表达增加。相反，在 EBRT 后 144 小时内可检测到 DU145 和 PC3 细胞中 PD-L1 表达的下降。 LNCaP 中未检测到 PD-L1。正常前列腺的上皮细胞不受辐射调节。通过与受辐射的 PCa 细胞相互作用，CTL 溶细胞活性和 IFN-γ 产生得到增强。最后，EBRT 未能阻止 IFN-γ 诱导的 PD-L1 上调。我们证明单剂量的 EBRT 可以增加人 PCa 细胞系中共刺激分子的表面表达并减少共抑制分子的表达。尽管 EBRT 未能降低 IFN-γ 诱导的 PD-L1 表达，但受辐射肿瘤细胞的变化导致 T 细胞活性的功能增强。这些数据表明，将放射疗法与 T 细胞刺激免疫疗法相结合可能是一种有吸引力的癌症治疗策略。
We sought to determine if single-dose external beam radiation therapy (EBRT) could modulate the expression signature of T-cell costimulatory and coinhibitory molecules in human prostate cancer (PCa) cell lines in vitro. We investigated the functional impact of irradiated PCa cells with a modulated costimulatory profile on responder T-cell activity. We used three PCa cell lines (DU145, PC3, and LNCaP) and two epithelial cell lines from noncancerous prostate and lung tissue. After 72 hours of EBRT, surface expression of four immunostimulatory molecules (CD70, CD275/ICOSL, CD134L/OX40L, and CD137L/41BBL) and two immunosuppressive markers (CTLA-4/CD152 and PD-L1/CD274) were evaluated by flow cytometry. We evaluated the impact of several radiation doses and the longevity of modulated expression. We examined the functional impact of radiation-induced modulation of cancer cells by cytotoxic T cells (CTL) cytotoxicity and ELISPOT assay for interferon-gamma (IFN-gamma) production. Last, we evaluated whether IFN-gamma-induced PD-L1 expression could be reversed by EBRT. After 10 Gy EBRT, expression of OX40L and 41BBL increased in all three PCa cell lines; expression of CD70 and ICOSL increased in PC3 cells. Conversely, a decrease in PD-L1 expression in DU145 and PC3 cells was detectable up to 144 hours after EBRT. No PD-L1 was detected in LNCaP. Epithelial cells from normal prostate were not modulated by radiation. CTL cytolytic activity and IFN-gamma production were enhanced by interaction with irradiated PCa cells. Finally, EBRT failed to prevent IFN-gamma-induced upregulation of PD-L1. We demonstrate that a single dose of EBRT increased surface expression of costimulatory molecules and decreased the expression of coinhibitory molecules in human PCa cell lines. Changes in irradiated tumor cells led to functional enhancement of T-cell activity, despite EBRT failing to reduce IFN-gamma-induced expression of PD-L1. These data suggest that combining radiotherapy with T-cell stimulating immunotherapy may be an attractive strategy for cancer treatment.