Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer
Immunogenic cell death by neoadjuvant oxaliplatin and radiation protects against metastatic failure in high-risk rectal cancer
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DOI：
10.1007/s00262-019-02458-x
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发表时间：
2020-03-01
影响因子：
5.8
通讯作者：
Ree, Anne Hansen
中科院分区：
文献类型：
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作者：
Bains, Simer J.;Abrahamsson, Hanna;Ree, Anne Hansen
目的局部进展期直肠癌的高系统性衰竭率要求合理使用常规治疗，以培养抗肿瘤免疫力。方法我们分析了高迁移率族蛋白-1（HMGB 1）蛋白，免疫原性细胞死亡（ICD）的指标，在诊断时和4周诱导化疗和5周序贯放化疗后，从50例患者的血浆中采样，这两种新辅助疗法均含有奥沙利铂。患者切除了残余肿瘤，并随访了长期结果。结果符合主要研究终点-无远处复发-的患者在诱导化疗和巩固化疗期间HMGB 1显著升高。ICD增加越高，转移失败风险越低（风险比0.26，95%置信区间0.11-0.62，P = 0.002）。然而，接受完整计划剂量奥沙利铂放化疗方案的患者的无转移生存期（P = 0.020）低于降低奥沙利铂剂量以避免放射输送破坏的患者，这对于维持有效的肿瘤细胞杀伤至关重要，在本例中，可能还保护了正在进行的放射依赖性ICD反应免受全身奥沙利铂毒性的影响。结论研究结果表明，全剂量诱导奥沙利铂，然后是适应的奥沙利铂剂量，符合全强度辐射诱导和维持ICD，因此，持久的无疾病结局的患者人群转移性进展的倾向。
Objective High rates of systemic failure in locally advanced rectal cancer call for a rational use of conventional therapies to foster tumor-defeating immunity. Methods We analyzed the high-mobility group box-1 (HMGB1) protein, a measure of immunogenic cell death (ICD), in plasma sampled from 50 patients at the time of diagnosis and following 4 weeks of induction chemotherapy and 5 weeks of sequential chemoradiotherapy, both neoadjuvant modalities containing oxaliplatin. The patients had the residual tumor resected and were followed for long-term outcome. Results Patients who met the main study end point-freedom from distant recurrence-showed a significant rise in HMGB1 during the induction chemotherapy and consolidation over the chemoradiotherapy. The higher the ICD increase, the lower was the metastatic failure risk (hazard ratio 0.26, 95% confidence interval 0.11-0.62, P = 0.002). However, patients who received the full-planned oxaliplatin dose of the chemoradiotherapy regimen had poorer metastasis-free survival (P = 0.020) than those who had the oxaliplatin dose reduced to avert breach of the radiation delivery, which is critical to maintain efficient tumor cell kill and in the present case, probably also protected the ongoing radiation-dependent ICD response from systemic oxaliplatin toxicity. Conclusion The findings indicated that full-dose induction oxaliplatin followed by an adapted oxaliplatin dose that was compliant with full-intensity radiation caused induction and maintenance of ICD and as a result, durable disease-free outcome for a patient population prone to metastatic progression.