Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy
Modulating the Tumor Microenvironment via Oncolytic Viruses and CSF-1R Inhibition Synergistically Enhances Anti-PD-1 Immunotherapy
复制标题
通过溶瘤病毒和 CSF-1R 抑制调节肿瘤微环境协同增强抗 PD-1 免疫治疗
DOI：
10.1016/j.ymthe.2018.11.010
复制
发表时间：
2019-01-02
影响因子：
12.4
通讯作者：
Deng, Hongxin
中科院分区：
文献类型：
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作者：
Shi, Gang;Yang, Qianmei;Deng, Hongxin
基于免疫检查点阻断的免疫治疗已成为最有前途的癌症治疗方法。然而，由于免疫抑制的肿瘤微环境，从免疫治疗中受益的结直肠癌患者的比例很小。因此，联合免疫治疗是克服这一局限性的理想策略。在这项研究中，我们开发了一种新的组合，即CSF-1R(集落刺激因子1受体)抑制剂(PLX3397)、溶瘤病毒和抗PD-1抗体。我们的结果表明，三联治疗协同给予显著的肿瘤控制和延长小鼠结肠癌模型的生存时间。分别携带CT26和MC38肿瘤的小鼠中，约有43%和82%的小鼠在三联治疗后长期存活。这种联合疗法通过增加T细胞在肿瘤中的渗透和增强抗肿瘤CD8(+)T细胞的功能，将免疫抑制的肿瘤微环境重新编程为以CD8(+)T细胞为导向的抗肿瘤免疫。我们的研究结果为临床联合治疗提供了强有力的策略。
Immunotherapy based on the immune checkpoint blockade has emerged as the most promising approach for cancer therapy. However, the proportion of colorectal cancer patients who benefit from immunotherapy is small due to the immunosuppressive tumor microenvironment. Hence, combination immunotherapy is an ideal strategy to overcome this limitation. In this study, we developed a novel combination of CSF-1R (colony-stimulating factor 1 receptor) inhibitor (PLX3397), oncolytic viruses, and anti-PD-1 antibody. Our results demonstrated that the triple treatment synergistically conferred significant tumor control and prolonged the survival of mouse models of colon cancer. Approximately 43% and 82% of mice bearing the CT26 and MC38 tumor, respectively, survived long term following the triple treatment. This combination therapy reprogrammed the immunosuppressive tumor microenvironment toward a CD8(+) T cell-biased anti-tumor immunity by increasing T cell infiltration in the tumor and augmenting anti-tumor CD8(+) T cell function. Our results provide a robust strategy for clinical combination therapy.