Augustine Titto, John Peter, Friedman Tyler, Jiffry Jeeshan, Guzik Hillary, Mannan Rifat, Gupta Riya, Delano Catherine, Mariadason John M, Zang Xingxing, Maitra Radhashree, Goel Sanjay
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, United States.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, United States.
Front Oncol. 2022 Oct 25;12:1018767. doi: 10.3389/fonc.2022.1018767. eCollection 2022.
The majority of colorectal cancers (CRCs) are microsatellite stable (MSS) and resistant to immunotherapy. The current study explores the possibility of using oncolytic reovirus to sensitize MSS CRC to immune checkpoint inhibition. While reovirus reduced metabolic activity among cells, microarray/computational analysis revealed microsatellite status-oriented activation of immune-response pathways. Reovirus plus anti-PD-1 treatment increased cell death among MSS cells . Reduced tumorigenicity and proliferative index, and increased apoptosis were evident among CT26 [MSS, ], but not in MC38 [microsatellite unstable/MSI, ] syngeneic mouse models under combinatorial treatment. PD-L1-PD-1 signaling axis were differentially altered among CT26/MC38 models. Combinatorial treatment activated the innate immune system, pattern recognition receptors, and antigen presentation markers. Furthermore, we observed the reduction of immunosuppressive macrophages and expansion of effector T cell subsets, as well as reduction in T cell exhaustion. The current investigation sheds light on the immunological mechanisms of the reovirus-anti-PD-1 combination to reduce the growth of MSS CRC.
大多数结直肠癌（CRC）是微卫星稳定（MSS）的，并且对免疫疗法耐药。当前研究探索了使用溶瘤呼肠孤病毒使MSS CRC对免疫检查点抑制敏感的可能性。虽然呼肠孤病毒降低了细胞间的代谢活性，但微阵列/计算分析显示了免疫反应途径的微卫星状态导向激活。呼肠孤病毒联合抗PD-1治疗增加了MSS细胞的细胞死亡。在联合治疗下，CT26 [MSS， ]同基因小鼠模型中肿瘤形成能力和增殖指数降低，细胞凋亡增加，但在MC38 [微卫星不稳定/MSI， ]同基因小鼠模型中未观察到这些现象。CT26/MC38模型中PD-L1-PD-1信号轴发生了不同改变。联合治疗激活了先天免疫系统、模式识别受体和抗原呈递标志物。此外，我们观察到免疫抑制性巨噬细胞减少，效应T细胞亚群扩增，以及T细胞耗竭减少。当前研究揭示了呼肠孤病毒-抗PD-1联合治疗减少MSS CRC生长的免疫机制。
