在食道癌中，表达PD-L1的癌相关成纤维细胞诱导肿瘤免疫抑制并导致临床预后不佳。
PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer.
发表日期：2023 Sep 05
作者：
Kento Kawasaki, Kazuhiro Noma, Takuya Kato, Toshiaki Ohara, Shunsuke Tanabe, Yasushige Takeda, Hijiri Matsumoto, Seitaro Nishimura, Tomoyoshi Kunitomo, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Hajime Kashima, Naoaki Maeda, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara
来源：
Cell Death & Disease
摘要：
编程细胞死亡1蛋白（PD-1）/编程细胞死亡配体1（PD-L1）轴在肿瘤免疫抑制中起着关键作用，而癌关联成纤维细胞（CAFs）具有多种促进肿瘤生长的功能。为了确定免疫治疗的优势，评估了肿瘤细胞与CAFs之间在PD-1/PD-L1轴上的关系。总体而言，对140例食管癌进行了PD-L1表达的免疫组化分析，并与α平滑肌肌动蛋白、成纤维细胞活化蛋白、CD8和forkhead box P3（FoxP3）阳性细胞的表达进行了关联分析。在体外评估了肿瘤细胞与CAFs之间的关系，并使用同基因小鼠模型评估了抗-PD-L1抗体的效果。生存分析显示，PD-L1+ CAF组的生存率较PD-L1-组较低。体外和体内实验证明，肿瘤细胞与CAFs之间的直接相互作用导致PD-L1表达互相上调。在体内实验中，抗-PD-L1抗体增加了死亡的CAFs和肿瘤细胞数量，导致CD8+ T细胞增加，FoxP3+ 调节性T细胞减少。我们证明了表达PD-L1的CAFs导致食管癌患者预后不良。肿瘤细胞和CAFs相互增强了PD-L1的表达，并诱导了肿瘤免疫抑制。因此，表达PD-L1的CAFs可能是肿瘤治疗的良好靶点，可以抑制肿瘤进展和改善宿主肿瘤免疫力。©2023年。作者。
The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.© 2023. The Author(s).