Celecoxib up-regulates the expression of the zeta chain of T cell receptor complex in tumor-infiltrating lymphocytes in human cervical cancer.

IF 10 1区 医学 Q1 ONCOLOGY
Gabriella Ferrandina, Franco Oreste Ranelletti, Francesco Legge, Vanda Salutari, Enrica Martinelli, Andrea Fattorossi, Domenica Lorusso, Gianfranco Zannoni, Valerio Vellone, Amelia Paglia, Giovanni Scambia
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引用次数: 15

Abstract

Purpose: We evaluated the effects of celecoxib treatment on tumor-infiltrating lymphocyte (TIL) subsets [CD3(+), CD4(+),CD8(+), CD25(+), and T cell receptor (TCR)-zeta-expressing cells] and tryptase-positive mast cells in cervical tumors. Circulating levels of cytokines [interleukin (IL)-1beta, IL-10, tumor necrosis factor-alpha, IL-6, and IL-12] and angiogenesis-modulating factors (vascular endothelial growth factor and endostatin) have also been analyzed.

Experimental design: Cervical tumor biopsies and blood samples were obtained at the time of diagnosis and after 10 days of celecoxib treatment (400 mg b.i.d., at 8:00 a.m. and 8:00 p.m.) in 27 cases. Immunohistochemistry and ELISA assays were used to assess the expression of biological factors in tumor tissue and circulating levels of cytokines and angiogenic molecules.

Results: We showed a statistically significant increase in the percentage of TIL expressing the TCR-zeta chain after celecoxib treatment: indeed, in cases exposed to celecoxib, the percentage of TCR-zeta(+) cells ranged from 5.0 to 50.0 (median, 22.5) with respect to baseline expression (range, 3.0-50.0; median, 10.0; P = 0.0016). There was no significant treatment-related difference in the percentage of CD3(+), CD4(+), CD8(+), and CD25(+) TIL as well as in tryptase-positive cells. IL-12 levels were significantly reduced in posttreatment samples with respect to baseline levels (P = 0.002). We also found a reduction in the circulating levels of vascular endothelial growth factor, and a statistically significant increase of serum endostatin levels (P = 0.035).

Conclusions: We reported the first evidence in humans that celecoxib restores zeta expression by TIL in primary cervical tumors, suggesting that a positive modulation of immune function may serve as an additional mechanism supporting the antitumor effect of this class of drugs.

塞来昔布上调宫颈癌肿瘤浸润淋巴细胞中T细胞受体复合物zeta链的表达。
目的:评价塞来昔布治疗对宫颈肿瘤肿瘤浸润淋巴细胞(TIL)亚群[CD3(+)、CD4(+)、CD8(+)、CD25(+)和T细胞受体(TCR)- ζ表达细胞]和胰蛋白酶阳性肥大细胞的影响。细胞因子[白细胞介素(IL)-1 β、IL-10、肿瘤坏死因子- α、IL-6和IL-12]和血管生成调节因子(血管内皮生长因子和内皮抑制素)的循环水平也被分析。实验设计:27例患者在诊断时和塞来昔布治疗10天后(400mg b.i.d,上午8点和晚上8点)进行宫颈肿瘤活检和血液取样。采用免疫组化和ELISA法检测肿瘤组织中生物因子的表达、细胞因子和血管生成分子的循环水平。结果:我们发现,塞来昔布治疗后,TIL表达TCR-zeta链的百分比有统计学意义的增加:事实上,在暴露于塞来昔布的病例中,TCR-zeta(+)细胞的百分比相对于基线表达(范围3.0-50.0;值,10.0;P = 0.0016)。CD3(+)、CD4(+)、CD8(+)和CD25(+) TIL以及胰蛋白酶阳性细胞的百分比在治疗相关方面没有显著差异。与基线水平相比,治疗后样本中IL-12水平显著降低(P = 0.002)。我们还发现血管内皮生长因子的循环水平降低,血清内皮抑制素水平有统计学意义的增加(P = 0.035)。结论:我们首次报道了塞来昔布在原发性宫颈肿瘤中通过TIL恢复zeta表达的证据,这表明免疫功能的正向调节可能是支持这类药物抗肿瘤作用的另一种机制。
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来源期刊
Clinical Cancer Research
Clinical Cancer Research 医学-肿瘤学
CiteScore
20.10
自引率
1.70%
发文量
1207
审稿时长
2.1 months
期刊介绍: Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.
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