Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy
Targeting CXCL12/CXCR4 and myeloid cells to improve the therapeutic ratio in patient-derived cervical cancer models treated with radio-chemotherapy
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DOI：
10.1038/s41416-019-0497-3
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发表时间：
2019-07-30
影响因子：
8.8
通讯作者：
Milosevic, Michael
中科院分区：
文献类型：
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作者：
Lecavalier-Barsoum, Magali;Chaudary, Naz;Milosevic, Michael
背景：趋化因子CXCL 12/CXCR 4通路参与宫颈癌的发病机制和放疗反应。我们之前报道过，放化疗（RTCT）和同时给予CXCR 4抑制剂普乐沙福可改善原发性肿瘤缓解。本研究的目的是确定最佳的RTCT和plerixafor的测序，负责改善反应和plerixafor对晚期肠toxicity.METHODS的效果的机制：原位宫颈癌异种移植物进行了治疗与RTCT（30戈伊，2戈伊分数和顺铂）有或无并发，辅助或连续plerixafor。终点是治疗结束时的生长延迟以及分子和免疫细胞变化。晚期肠毒性进行了评估，通过组织学检查直肠90天后，一个单一的20戈伊fraction.Results：RTCT增加CXCL 12/CXCR 4信号和髓样细胞的肿瘤内积累，除了plerixafor减轻这些影响。所有RTCT和plerixafor组与RTCT单药治疗相比均显示肿瘤生长延迟延长，其中辅助治疗组的改善最大。Plerixafor还降低了晚期肠毒性。结论：将Plerixafor加入RTCT中可减弱治疗诱导的CXCL 12/CXCR 4信号传导增加，改善原发性肿瘤反应并减少肠道副作用。这种组合保证在未来的临床试验中进行测试。
BACKGROUND: The CXCL12/CXCR4 chemokine pathway is involved in cervical cancer pathogenesis and radiation treatment (RT) response. We previously reported that radiochemotherapy (RTCT) and concurrent administration of the CXCR4 inhibitor plerixafor improved primary tumour response. The aims of this study were to determine optimal sequencing of RTCT and plerixafor, the mechanisms responsible for improved response and the effect of plerixafor on late intestinal toxicity.METHODS: Orthotopic cervical cancer xenografts were treated with RTCT (30 Gy in 2 Gy fractions and cisplatin) with or without concurrent, adjuvant or continuous plerixafor. The endpoints were growth delay and molecular and immune cell changes at the end of treatment. Late intestinal toxicity was assessed by histologic examination of the rectum 90 days after a single 20 Gy fraction.RESULTS: RTCT increased CXCL12/CXCR4 signalling and the intratumoral accumulation of myeloid cells; the addition of plerixafor mitigated these effects. All of the RTCT and plerixafor arms showed prolonged tumour growth delay compared to RTCT alone, with the adjuvant arm showing the greatest improvement. Plerixafor also reduced late intestinal toxicity.CONCLUSION: Adding Plerixafor to RTCT blunts treatment-induced increases in CXCL12/CXCR4 signalling, improves primary tumour response and reduces intestinal side effects. This combination warrants testing in future clinical trials.