Hu Aiyan, Ding Miao, Zhu Jianmin, Liu Jin-Qing, Pan Xueliang, Ghoshal Kalpana, Bai Xue-Feng
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, United States.
Front Cell Dev Biol. 2020 Mar 27;8:210. doi: 10.3389/fcell.2020.00210. eCollection 2020.
IL-27 is an anti-inflammatory cytokine that has been shown to have potent anti-tumor activity. We recently reported that systemic delivery of IL-27 using recombinant adeno-associated virus (rAAV) induced depletion of Tregs and significantly enhanced the efficacy of cancer immunotherapy in a variety of mouse tumor models. A potential caveat of systemic delivery of IL-27 using rAAV is that there is no practical method to terminate IL-27 production when its biological activity is no longer needed. Therefore, in this work, we tested if directly injecting AAV-IL-27 into tumors could lead to similar anti-tumor effect yet avoiding uncontrolled IL-27 production. We found that high levels of IL-27 was produced in tumors and released to peripheral blood after AAV-IL-27 intra-tumoral injection. AAV-IL-27 local therapy showed potent anti-tumor activity in mice bearing plasmacytoma J558 tumors and modest anti-tumor activity in mice bearing B16.F10 tumors. Intra-tumoral injection of AAV-IL-27 induced infiltration of immune effectors including CD8 T cells and NK cells into tumors, caused systemic reduction of Tregs and stimulated protective immunity. Mechanistically, we found that IL-27 induced T cell expression of CXCR3 in an IL-27R-dependent manner. Additionally, we found that AAV-IL-27 local therapy had significant synergy with anti-PD-1 or T cell adoptive transfer therapy. Importantly, in mice whose tumors were completely rejected, IL-27 serum levels were significantly reduced or diminished. Thus, intra-tumoral injection of AAV-IL-27 is a feasible approach that can be used alone and in combination with anti-PD-1 antibody or T cell adoptive transfer for the treatment of cancer.
白细胞介素-27（IL-27）是一种抗炎细胞因子，已被证明具有强大的抗肿瘤活性。我们最近报道，使用重组腺相关病毒（rAAV）全身递送IL-27可诱导调节性T细胞（Tregs）耗竭，并在多种小鼠肿瘤模型中显著增强癌症免疫治疗的疗效。使用rAAV全身递送IL-27的一个潜在问题是，当不再需要其生物活性时，没有切实可行的方法来终止IL-27的产生。因此，在这项研究中，我们测试了直接向肿瘤内注射AAV-IL-27是否能产生类似的抗肿瘤效果，同时避免IL-27的不受控制的产生。我们发现，在AAV-IL-27瘤内注射后，肿瘤中产生了高水平的IL-27并释放到外周血中。AAV-IL-27局部治疗在携带浆细胞瘤J558肿瘤的小鼠中显示出强大的抗肿瘤活性，在携带B16.F10肿瘤的小鼠中显示出适度的抗肿瘤活性。瘤内注射AAV-IL-27可诱导包括CD8 T细胞和自然杀伤细胞（NK细胞）在内的免疫效应细胞浸润到肿瘤中，导致Tregs的全身减少并刺激保护性免疫。从机制上讲，我们发现IL-27以IL-27受体（IL-27R）依赖的方式诱导T细胞表达CXC趋化因子受体3（CXCR3）。此外，我们发现AAV-IL-27局部治疗与抗程序性死亡蛋白1（anti-PD-1）或T细胞过继性转移治疗具有显著协同作用。重要的是，在肿瘤被完全排斥的小鼠中，IL-27血清水平显著降低或消失。因此，瘤内注射AAV-IL-27是一种可行的方法，可单独使用或与抗PD-1抗体或T细胞过继性转移联合用于癌症治疗。
