Chen Duo, Huang Luyu, Zhou Haiyu, Zhang Yuhui
Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
Division of Thoracic Surgery, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.
Front Immunol. 2021 Feb 26;12:615089. doi: 10.3389/fimmu.2021.615089. eCollection 2021.
Oncolytic viruses are of growing importance in cancer therapeutics since they combine direct oncolytic effect and the stimulation of antitumor immunity. Emerging evidences showed that the function of oncolytic viruses is dependent on immune response in tumor microenvironment, and the modulation of immunity could influence their efficacy. Here we combined the interleukin 10 (IL-10) and oncolytic adenovirus Ad-hTERT to treat lung cancer and explored the underlying mechanism under combination therapy. Lewis lung carcinoma (LLC) and B16F10 tumor-bearing immunocompetent C57BL/6 mice that received Ad-hTERT or IL-10 alone showed mild antitumor effect, while the combination therapy shrink tumor bulks and prolonged survival remarkably. In addition, IL-10 didn't show direct influence on tumor cell viability or Ad-hTERT mediated tumor cell lysis . To further explore the influence of combination therapy mediated antitumor capacity, we eliminated CD8 T, CD4 T or natural killer (NK) cells in LLC and B16F10-bearing C57BL/6 mice, and found that CD8 T cells were critical mediator in the combination therapy. The combination therapy induced intensive infiltration of CD8 T cells in tumors, increased tumor-specific IFN-γ secretion by CD8 T cells. The long-term tumor-specific immune memory induced by the combination therapy rejected rechallenge by respective tumor cell lines. This study demonstrated that the therapy combining IL-10 and Ad-hTERT augmented antitumor efficacy which was CD8 T cells dependent. Our findings paved the way to combine cytokines and oncolytic viruses to enhance antitumor immunotherapy in treating cancer.
溶瘤病毒在癌症治疗中的重要性日益凸显，因为它们兼具直接的溶瘤作用和刺激抗肿瘤免疫的功能。新出现的证据表明，溶瘤病毒的功能取决于肿瘤微环境中的免疫反应，而免疫调节会影响其疗效。在此，我们将白细胞介素10（IL-10）与溶瘤腺病毒Ad-hTERT联合用于治疗肺癌，并探索联合治疗的潜在机制。单独接受Ad-hTERT或IL-10治疗的荷Lewis肺癌（LLC）和B16F10肿瘤的免疫健全C57BL/6小鼠显示出轻微的抗肿瘤作用，而联合治疗显著缩小了肿瘤体积并延长了生存期。此外，IL-10对肿瘤细胞活力或Ad-hTERT介导的肿瘤细胞裂解没有直接影响。为了进一步探究联合治疗介导的抗肿瘤能力的影响，我们在荷LLC和B16F10的C57BL/6小鼠中清除了CD8 T细胞、CD4 T细胞或自然杀伤（NK）细胞，发现CD8 T细胞是联合治疗中的关键介质。联合治疗诱导了CD8 T细胞在肿瘤中的密集浸润，增加了CD8 T细胞分泌的肿瘤特异性干扰素-γ。联合治疗诱导的长期肿瘤特异性免疫记忆排斥了相应肿瘤细胞系的再次攻击。本研究表明，IL-10与Ad-hTERT联合治疗增强了抗肿瘤疗效，且该疗效依赖于CD8 T细胞。我们的研究结果为联合细胞因子和溶瘤病毒以增强癌症治疗中的抗肿瘤免疫疗法铺平了道路。
