Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors.
Wnt Inhibition Sensitizes PD-L1 Blockade Therapy by Overcoming Bone Marrow-Derived Myofibroblasts-Mediated Immune Resistance in Tumors.
复制标题
Wnt 抑制通过克服肿瘤中骨髓源性肌成纤维细胞介导的免疫抵抗来增强 PD-L1 阻断疗法的敏感性
DOI：
10.3389/fimmu.2021.619209
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发表时间：
2021
影响因子：
7.3
通讯作者：
Tu S
中科院分区：
文献类型：
--
作者：
Huang T;Li F;Cheng X;Wang J;Zhang W;Zhang B;Tang Y;Li Q;Zhou C;Tu S
癌症相关成纤维细胞（CAF）已被认为是肿瘤对免疫检查点阻断疗法产生耐药性的原因之一，但其潜在机制仍不清楚。在本研究中，通过将BMF和肿瘤细胞皮下混合接种到小鼠中，成功建立了富含骨髓源性CAF（BMF）的肿瘤模型，并且与单纯的肿瘤异种移植物相比，证明了BMF混合的肿瘤异种移植物对抗PD-L1抗体免疫治疗具有抗性。通过BMF和肿瘤细胞的共培养系统的体外测定表明，共培养的BMF被诱导过表达PD-L1，而在共培养的癌细胞中没有这种现象。BMF中PD-L1的进一步敲除挽救了BMF混合肿瘤异种移植物对PD-L1阻断疗法的敏感性。从机制上讲，通过微阵列测定，我们确定了由癌细胞刺激的BMF中PD-L1的上调是通过BMF中Wnt/β-连环蛋白信号通路的激活来介导的。此外，施用Wnt/β-连环蛋白信号传导抑制剂，包括XAV-939和Wnt-C59，明显抑制共培养的BMF中PD-L1表达的上调。XAV-939的进一步组合施用显著增强了BMF混合肿瘤中PD-L1阻断疗法的治疗结果。总之，我们的研究表明，Wnt抑制通过克服BMF介导的免疫疗法抗性来增强PD-L1阻断功效。
Cancer-associated fibroblasts (CAFs) has been recognized as one cause of tumor resistance to immune checkpoint blockade therapy, but the underlying mechanisms still remain elusive. In the present study, a bone marrow-derived CAF (BMF) -rich tumor model is successfully established by subcutaneously mixed inoculation of BMFs and tumor cells into mice and the BMF-mixed tumor xenografts are demonstrated to be resistant to anti-PD-L1 antibody immunotherapy compared to the mere tumor xenografts. In vitro assays via the co-culture system of BMFs and tumor cells indicate that the co-cultured BMFs are induced to overexpress PD-L1, while there is no such a phenomenon in the co-cultured cancer cells. The further knock-out of PD-L1 in BMFs rescues the sensitivity of BMF-mixed tumor xenografts to PD-L1 blockade therapy. Mechanistically, via the microarray assay, we identify that the upregulation of PD-L1 in BMFs stimulated by cancer cells is medicated by the activation of the Wnt/β-catenin signaling pathway in BMFs. Moreover, the administration of Wnt/β-catenin signaling inhibitors, including XAV-939 and Wnt-C59, distinctly inhibits the upregulation of PD-L1 expression in the co-cultured BMFs. The further combination administration of XAV-939 significantly potentiates the therapeutic outcome of PD-L1 blockade therapy in BMF-mixed tumors. In summary, our study demonstrates that Wnt inhibition augments PD-L1 blockade efficacy by overcoming BMF-mediated immunotherapy resistance.