IFNγ/PD-L1 Signaling Improves the Responsiveness of Anti-PD-1 Therapy in Colorectal Cancer: An in vitro Study.
IFNγ/PD-L1 Signaling Improves the Responsiveness of Anti-PD-1 Therapy in Colorectal Cancer: An in vitro Study.
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IFNγ/PD-L1 信号传导改善结直肠癌抗 PD-1 治疗的反应性：一项体外研究。
DOI：
10.2147/ott.s294136
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发表时间：
2021
影响因子：
4
通讯作者：
He H
中科院分区：
文献类型：
--
作者：
Yuan W;Deng D;Li H;Hu X;Shang X;Hou X;Jiang H;He H
程序性细胞死亡1配体1（PD-L1）可通过肿瘤微环境中的干扰素γ（IFNγ）在癌细胞中上调。IFNγ/PD-L1信号传导与黑色素瘤患者对免疫检查点阻断的应答相关我们的前期研究表明，微卫星不稳定性高（MSI-H）细胞系可能对IFNγ治疗表现出选择性高反应性，这有助于增加PD-L1表达，并可能是结直肠癌对抗PD-1治疗的反应机制。本研究评估了IFNγ处理的一组MSI和微卫星稳定性（MSS）细胞系中PD-L1的表达。同时对IFNγ高反应性中与信号转导和转录激活因子（STAT）相关的差异信号分子进行了研究。此外，我们建立了一种含有PD-L1表达较高的CT 26细胞和外周血单个核细胞（PBMC）的体外共培养试验。证实了响应于抗PD-1治疗的癌细胞活力以及细胞凋亡状态的变化。在共培养试验中，我们进一步观察了PD-1免疫治疗后CD 4+和CD 8+淋巴细胞百分比的变化。最后，还研究了测定中炎症和适应性免疫因子的平均程度。这项体外研究表明，MSI细胞系可能对IFNγ暴露表现出高反应性，IFNγ主要通过增加STAT 1和减少STAT 3信号转导诱导PD-L1上调。IFNγ/PD-L1信号主要通过CTL谱参与抗PD-1治疗的应答。我们的研究结果加强了先前的知识，即对免疫检查点阻断的反应主要发生在具有预先存在的肿瘤内IFNγ/PD-L1信号的患者中，因此建议了潜在的治疗策略，以增强大多数结直肠癌患者对PD-1阻断免疫治疗的反应性。
Programmed cell death 1 ligand 1 (PD-L1) can be upregulated in cancer cells via interferon gamma (IFNγ) in the tumor microenvironment. IFNγ/PD-L1 signaling is associated with the response to immune checkpoint blockade in melanoma patients. Our previous investigation indicated that the microsatellite instability-high (MSI-H) cell line might exhibit selective hyperresponsiveness to IFNγ treatment, which contributes to increased PD-L1 expression and may be a mechanism of response to anti-PD-1 therapy in colorectal cancer. The present study evaluated the expression of PD-L1 in a set of MSI and microsatellite stability (MSS) cell lines with IFNγ treatment. The differential signaling molecules associated with signal transducer and activator of transcription (STAT) contributing to hyperresponsiveness to IFNγ exposure were also investigated. Furthermore, we established a coculture assay containing CT26 cells with higher expression of PD-L1 and peripheral blood mononuclear cells (PBMCs) in vitro. Changes in cancer cell viability as well as apoptosis status in response to anti-PD-1 therapy were demonstrated. We further observed changes in the percentage of CD4+ and CD8+ lymphocytes after PD-1 immunotherapy in the coculture assay. Finally, the average extent of inflammation and adaptive immunity factors in the assay was also investigated. This in vitro study revealed that the MSI cell line might exhibit hyperresponsiveness to IFNγ exposure, and IFNγ induced upregulation of PD-L1 mainly through increased STAT1 and decreased STAT3 signaling. IFNγ/PD-L1 signaling participated in the response to anti-PD-1 therapy mainly through the CTL profile. Our findings reinforce previous knowledge of the fact that the response to immune checkpoint blockade occurs mainly in patients with a preexisting intratumoral IFNγ/PD-L1 signal, thus suggesting potential therapeutic strategies to enhance responsiveness to PD-1 blockade immunotherapy in most patients with colorectal cancer.