State Key Laboratory of Oncogenes and Related Genes, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Front Immunol. 2021 Mar 15;12:619209. doi: 10.3389/fimmu.2021.619209. eCollection 2021.
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 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, 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.
癌症相关成纤维细胞（CAFs）已被认为是肿瘤对免疫检查点阻断治疗产生耐药性的原因之一，但潜在机制仍不清楚。在本研究中，通过将 CAFs 和肿瘤细胞皮下混合接种到小鼠中，成功建立了富含骨髓来源 CAFs（BMFs）的肿瘤模型，并证明与单纯肿瘤异种移植物相比，BMF 混合肿瘤异种移植物对抗 PD-L1 抗体免疫治疗具有耐药性。体外实验中，CAFs 和肿瘤细胞共培养系统表明，共培养的 BMFs 被诱导过度表达 PD-L1，而共培养的癌细胞则没有这种现象。进一步敲除 BMFs 中的 PD-L1 可恢复 BMF 混合肿瘤异种移植物对 PD-L1 阻断治疗的敏感性。在机制上，通过微阵列分析，我们发现癌细胞刺激的 BMFs 中 PD-L1 的上调是由 BMFs 中 Wnt/β-连环蛋白信号通路的激活介导的。此外，Wnt/β-连环蛋白信号抑制剂，包括 XAV-939 和 Wnt-C59，可明显抑制共培养的 BMFs 中 PD-L1 表达的上调。XAV-939 的进一步联合给药显著增强了 PD-L1 阻断治疗在 BMF 混合肿瘤中的治疗效果。总之，我们的研究表明，Wnt 抑制通过克服 CAFs 介导的免疫治疗耐药性增强了 PD-L1 阻断治疗的疗效。
