Du Four Stephanie, Maenhout Sarah K, Niclou Simone P, Thielemans Kris, Neyns Bart, Aerts Joeri L
Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel Laarbeeklaan 103E, 1090, Brussels, Belgium.
NORLUX Neuro-Oncology Laboratory, Luxembourg Institute of Health (LIH) Luxembourg.
Am J Cancer Res. 2016 Nov 1;6(11):2514-2531. eCollection 2016.
Melanoma brain metastases (MBM) occur in 10% to 50% of melanoma patients. They are often associated with a high morbidity and despite the improvements in the treatment of advanced melanoma, including immunotherapy, patients with MBM still have a poor prognosis. Antiangiogenic treatment was shown to reduce the immunosuppressive tumor microenvironment. Therefore we investigated the effect of the combination of VEGFR- and CTLA-4 blockade on the immune cells within the tumor microenvironment. In this study we investigated the effect of the combination of axitinib, a TKI against VEGFR-1, -2 and -3, with therapeutic inhibition of CTLA-4 in subcutaneous and intracranial mouse melanoma models. The combination of axitinib with αCTLA-4 reduced tumor growth and increased survival in both intracranial and subcutaneous models. Investigation of the splenic immune cells showed an increased number of CD4 and CD8 T cells after combination treatment. Moreover, combination treatment increased the number of intratumoral dendritic cells (DCs) and monocytic myeloid-derived suppressor cells (moMDSCs). When these immune cell populations were sorted from the subcutaneous and intracranial tumors of mice treated with axitinib+αCTLA-4, we observed an increased antigen-presenting function of DCs and a reduced suppressive capacity of moMDSCs on a per cell basis. Our results suggest that the combination of antiangiogenesis and checkpoint inhibition can lead to an enhanced antitumor effect leading to increased survival. We found that this effect is in part due to an enhanced antitumor immune response generated by an increased antigen-presenting function of intratumoral DCs in combination with a reduced suppressive capacity of intratumoral moMDSCs.
黑色素瘤脑转移(MBM)发生于10%至50%的黑色素瘤患者中。它们常与高发病率相关,尽管包括免疫疗法在内的晚期黑色素瘤治疗有所改善,但MBM患者的预后仍然很差。抗血管生成治疗已显示可减少免疫抑制性肿瘤微环境。因此,我们研究了VEGFR阻断与CTLA-4阻断联合对肿瘤微环境中免疫细胞的影响。在本研究中,我们在皮下和颅内小鼠黑色素瘤模型中研究了阿昔替尼(一种针对VEGFR-1、-2和-3的酪氨酸激酶抑制剂)与CTLA-4治疗性抑制联合使用的效果。阿昔替尼与αCTLA-4联合使用在颅内和皮下模型中均降低了肿瘤生长并提高了生存率。对脾脏免疫细胞的研究表明,联合治疗后CD4和CD8 T细胞数量增加。此外,联合治疗增加了肿瘤内树突状细胞(DCs)和单核细胞来源的髓系抑制细胞(moMDSCs)的数量。当从接受阿昔替尼+αCTLA-4治疗的小鼠的皮下和颅内肿瘤中分离出这些免疫细胞群体时,我们观察到DCs的抗原呈递功能增强,而moMDSCs的单个细胞抑制能力降低。我们的结果表明,抗血管生成和检查点抑制联合可导致增强的抗肿瘤作用,从而提高生存率。我们发现这种作用部分归因于肿瘤内DCs抗原呈递功能增强与肿瘤内moMDSCs抑制能力降低共同产生的增强的抗肿瘤免疫反应。