CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Inhibition of FAK promotes pancreatic cancer immunotherapy by mediating CXCL10 secretion to enhance CD8(+) T cell infiltration.
Inhibition of FAK promotes pancreatic cancer immunotherapy by mediating CXCL10 secretion to enhance CD8(+) T cell infiltration.
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免疫治疗在治疗多种恶性肿瘤方面已显示出潜力，但其在胰腺癌（PC）中的疗效仍然有限，可能是由于PC致密的基质成分和免疫抑制微环境所致。黏着斑激酶（FAK）是一种非受体酪氨酸激酶，在肿瘤微环境和细胞内信号通路中发挥关键作用。
然而，FAK在PC发生和发展中的具体作用，以及其对肿瘤免疫微环境（TIM）的调控机制，仍未完全阐明。在本研究中，我们分析了单细胞测序数据集和临床标本，以评估FAK在PC免疫应答中的作用。
我们使用患者来源类器官（PDO）与免疫细胞的共培养体系，验证了FAK改变对CD8 + T细胞浸润的影响。此外，我们建立了小鼠PC模型和双人源化模型，以研究FAK的体内功能及其抑制剂用于免疫治疗的潜力。
我们的结果表明，FAK与PC中的免疫抑制微环境相关。抑制FAK可通过促进PC中CXCL10分泌来增强CD8 + T细胞浸润。
此外，FAK抑制剂与免疫检查点抑制剂联合使用时表现出协同抗肿瘤作用。本研究探讨了FAK作为治疗靶点的潜力，尤其是其在调节TIM中的作用，从而为PC的治疗提供了新的研究方向。
Immunotherapy has demonstrated potential in treating various malignant tumors, but its efficacy in pancreatic cancer (PC) remains limited, possibly due to the dense stromal components and immunosuppressive microenvironment of PC. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a crucial role in the tumor microenvironment and intracellular signaling pathways.
However, the specific role of FAK in the development and progression of PC, as well as its regulatory mechanisms on the tumor immune microenvironment (TIM), are still not fully understood. In this study, we analyzed single-cell sequencing datasets and clinical specimens to evaluate the role of FAK in the immune response of PC.
We verified the impact of FAK alterations on CD8 + T cell infiltration using a co-culture system of patient-derived organoids (PDO) and immune cells.
Additionally, mouse PC models and dual humanized models are established to investigate the in vivo function of FAK and the potential of its inhibitors for immunotherapy.
Our results demonstrate that FAK is associated with the immunosuppressive microenvironment in PC. Inhibiting FAK enhances CD8 + T cell infiltration by promoting CXCL10 secretion in PC.
Moreover, FAK inhibitors exhibit a synergistic anti-tumor effect when combined with immune checkpoint inhibitors.
This study explores the potential of FAK as a therapeutic target, particularly its role in modulating TIM, thereby providing new research directions for the treatment of PC.
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