Liu Weilin, Dai Enyong, Liu Zuqiang, Ma Congrong, Guo Zong Sheng, Bartlett David L
The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Mol Ther Oncolytics. 2020 Apr 21;17:350-360. doi: 10.1016/j.omto.2020.04.006. eCollection 2020 Jun 26.
Successful therapeutic vaccination would allow locally delivered oncolytic virus (OV) to exert systemic immunologic effects on metastases and improve survival. We have utilized bilateral flank tumor models to determine the most efficacious regimens of vaccination. Intratumoral injection with membrane-tethered interleukin -2-armed OV (vvDD-mIL2) plus a Toll-like receptor 9 ligand (CpG) yielded systemic immunization and decreased tumor growth in a contralateral, noninjected tumor. Our main aims were to study the tumor immune microenvironment (TME) after vaccination and identify additional immune adjuvants that may improve the systemic tumor-specific immunity. Immunological profiles in the spleen showed an increased CD8 T cell/regulatory T cell (Treg) ratio and increased CD11c cells after dual injection in one flank tumor. Concurrently, there was increased infiltration of tumor necrosis factor alpha (TNF-α)CD8 T cells and interferon gamma (IFN-γ)CD4 T cells and reduced CTLA-4PD-1CD8 T cells in the contralateral, noninjected tumor. The anti-tumoral activity depended on CD8 T cells and IFN-γ, but not CD4 T cells. Based on the negative immune components still existing in the untreated tumors, we investigated additional adjuvants: clodronate liposome-mediated depletion of macrophages plus anti-PD-1 therapy. This regimen dramatically reduced the tumor burden in the noninjected tumor and increased median survival by 87%, suggesting that inhibition/elimination of suppressive components in the tumor microenvironment (TME) can improve therapeutic outcomes. This study emphasizes the importance of immune profiling to design rational, combined immunotherapy regimens ultimately to impact patient survival.
成功的治疗性疫苗接种将使局部递送的溶瘤病毒（OV）对转移灶产生全身免疫效应并提高生存率。我们利用双侧侧翼肿瘤模型来确定最有效的疫苗接种方案。瘤内注射膜 tethered 白细胞介素 -2 武装的 OV（vvDD-mIL2）加 Toll 样受体 9 配体（CpG）可产生全身免疫，并降低对侧未注射肿瘤的生长。我们的主要目的是研究疫苗接种后的肿瘤免疫微环境（TME），并确定可能改善全身肿瘤特异性免疫的其他免疫佐剂。一侧侧翼肿瘤双注射后，脾脏的免疫谱显示 CD8 T 细胞/调节性 T 细胞（Treg）比例增加，CD11c 细胞增加。同时，对侧未注射肿瘤中肿瘤坏死因子α（TNF-α）CD8 T 细胞和干扰素γ（IFN-γ）CD4 T 细胞的浸润增加，CTLA-4PD-1CD8 T 细胞减少。抗肿瘤活性依赖于 CD8 T 细胞和 IFN-γ，而不是 CD4 T 细胞。基于未治疗肿瘤中仍然存在的负性免疫成分，我们研究了其他佐剂：氯膦酸脂质体介导的巨噬细胞清除加抗 PD-1 治疗。该方案显著降低了未注射肿瘤的肿瘤负担，并使中位生存期延长了 87%，表明抑制/消除肿瘤微环境（TME）中的抑制成分可改善治疗效果。本研究强调了免疫谱分析对于设计合理的联合免疫治疗方案以最终影响患者生存的重要性。
