Department of Pathology, Shanghai Tenth People's Hospital Affiliated to Tongji University, 200072, Shanghai, China.
Department of Oncology, Shanghai Tenth People's Hospital Affiliated to Tongji University, 200072, Shanghai, China.
Signal Transduct Target Ther. 2021 Nov 19;6(1):398. doi: 10.1038/s41392-021-00795-x.
Given that only a subset of patients with colorectal cancer (CRC) benefit from immune checkpoint therapy, efforts are ongoing to identify markers that predict immunotherapeutic response. Increasing evidence suggests that microbes influence the efficacy of cancer therapies. Fusobacterium nucleatum induces different immune responses in CRC with different microsatellite-instability (MSI) statuses. Here, we investigated the effect of F. nucleatum on anti-PD-L1 therapy in CRC. We found that high F. nucleatum levels correlate with improved therapeutic responses to PD-1 blockade in patients with CRC. Additionally, F. nucleatum enhanced the antitumor effects of PD-L1 blockade on CRC in mice and prolonged survival. Combining F. nucleatum supplementation with immunotherapy rescued the therapeutic effects of PD-L1 blockade. Furthermore, F. nucleatum induced PD-L1 expression by activating STING signaling and increased the accumulation of interferon-gamma (IFN-γ) CD8 tumor-infiltrating lymphocytes (TILs) during treatment with PD-L1 blockade, thereby augmenting tumor sensitivity to PD-L1 blockade. Finally, patient-derived organoid models demonstrated that increased F. nucleatum levels correlated with an improved therapeutic response to PD-L1 blockade. These findings suggest that F. nucleatum may modulate immune checkpoint therapy for CRC.
鉴于只有一部分结直肠癌（CRC）患者受益于免疫检查点治疗，目前正在努力寻找预测免疫治疗反应的标志物。越来越多的证据表明，微生物会影响癌症治疗的效果。具核梭杆菌在具有不同微卫星不稳定性（MSI）状态的 CRC 中诱导不同的免疫反应。在这里，我们研究了具核梭杆菌对 CRC 中抗 PD-L1 治疗的影响。我们发现，高水平的具核梭杆菌与 CRC 患者对 PD-1 阻断的治疗反应改善相关。此外，具核梭杆菌增强了 PD-L1 阻断对小鼠 CRC 的抗肿瘤作用，并延长了生存时间。将具核梭杆菌补充与免疫治疗相结合，挽救了 PD-L1 阻断的治疗效果。此外，具核梭杆菌通过激活 STING 信号诱导 PD-L1 表达，并在 PD-L1 阻断治疗期间增加干扰素-γ（IFN-γ）CD8 肿瘤浸润淋巴细胞（TIL）的积累，从而增强肿瘤对 PD-L1 阻断的敏感性。最后，患者来源的类器官模型表明，具核梭杆菌水平的增加与对 PD-L1 阻断的治疗反应改善相关。这些发现表明，具核梭杆菌可能调节 CRC 的免疫检查点治疗。
