Pfannenstiel Lukas W, McNeilly Corey, Xiang Chaomei, Kang Kai, Diaz-Montero Claudia Marcella, Yu Jennifer S, Gastman Brian R
Department of Immunology, Lerner Research Institute, Cleveland, OH, USA.
Department of Stem Cell Biology and Regenerative Medicine, Cleveland, OH, USA.
Oncoimmunology. 2018 Oct 11;8(1):e1507669. doi: 10.1080/2162402X.2018.1507669. eCollection 2019.
Nearly half of melanoma patients develop brain metastases during the course of their disease. Despite advances in both localized radiation and systemic immunotherapy, brain metastases remain difficult to treat, with most patients surviving less than 5 months from the time of diagnosis. While both treatment regimens have individually shown considerable promise in treating metastatic melanoma, there is interest in combining these strategies to take advantage of potential synergy. In order to study the ability of local radiation and anti-PD-1 immunotherapy to induce beneficial anti-tumor immune responses against distant, unirradiated tumors, we used two mouse models of metastatic melanoma in the brain, representing BRAF mutant and non-mutant tumors. Combination treatments produced a stronger systemic anti-tumor immune response than either treatment alone. This resulted in reduced tumor growth and larger numbers of activated, cytotoxic CD8 T cells, even in the unirradiated tumor, indicative of an abscopal effect. The immune-mediated effects were present regardless of BRAF status. These data suggest that irradiation of brain metastases and anti-PD-1 immunotherapy together can induce abscopal anti-tumor responses that control both local and distant disease.
近一半的黑色素瘤患者在病程中会发生脑转移。尽管局部放疗和全身免疫治疗都取得了进展,但脑转移瘤仍然难以治疗,大多数患者从诊断时起存活时间不到5个月。虽然这两种治疗方案在治疗转移性黑色素瘤方面各自都显示出了相当大的前景,但人们有兴趣将这些策略结合起来,以利用潜在的协同作用。为了研究局部放疗和抗PD-1免疫治疗诱导针对远处未受照射肿瘤的有益抗肿瘤免疫反应的能力,我们使用了两种脑转移性黑色素瘤小鼠模型,分别代表BRAF突变型和非突变型肿瘤。联合治疗产生的全身抗肿瘤免疫反应比单独任何一种治疗都更强。这导致肿瘤生长减缓,活化的细胞毒性CD8 T细胞数量增加,即使在未受照射的肿瘤中也是如此,这表明存在远隔效应。无论BRAF状态如何,均存在免疫介导的效应。这些数据表明,脑转移瘤放疗和抗PD-1免疫治疗联合应用可诱导控制局部和远处疾病的远隔抗肿瘤反应。