Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University of Toronto, Toronto, Ontario, Canada.
Department of General Surgery, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
Clin Cancer Res. 2017 Sep 15;23(18):5502-5513. doi: 10.1158/1078-0432.CCR-17-0438. Epub 2017 Jun 12.
How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade. We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery. Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8 T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4 T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade. A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. .
目前尚不清楚如何最好地将免疫疗法与标准护理相结合。具有加速非消融性亚分次放射治疗随后进行手术的临床方案可能为实施免疫检查点阻断提供机会。因此，我们在小鼠间皮瘤模型中评估了非消融性亚分次放射治疗与手术联合对免疫系统的影响。钝性手术（R1 切除术）用于分析短期效应，根治性手术（R0 切除术）用于分析手术前该放射方案的长期效应。非消融性亚分次放射治疗导致针对肿瘤的特异性免疫激活，与 CD8 T 细胞的显著上调相关，从而限制了不完全切除的负面影响。在根治性手术前 7 天进行相同的放射方案导致了长期的抗肿瘤免疫保护，主要由 CD4 T 细胞驱动。单独进行根治性手术或在根治性手术前 24 小时完成短期非消融性放射治疗均不能提供这种疫苗效应。将该放射方案与 CTLA-4 阻断联合使用提供了比单独放射更好的效果。与该放射方案联合使用 PD-1 或 PD-L1 阻断的效果不如与 CTLA-4 阻断联合使用的效果好。针对肿瘤的免疫系统的特异性激活有助于加速、术前亚分次放射治疗的获益。非消融性亚分次放射治疗联合手术为在临床环境中引入免疫检查点阻断提供了机会。
