T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumor immunity
T-cell co-stimulation in combination with targeting FAK drives enhanced anti-tumor immunity
复制标题
DOI：
10.7554/elife.48092
复制
发表时间：
2020-01-21
期刊：
影响因子：
7.7
通讯作者：
Serrels, Alan
中科院分区：
文献类型：
--
作者：
Canel, Marta;Taggart, David;Serrels, Alan
粘着斑激酶（FAK）抑制剂目前正在与抗PD-1免疫检查点抑制剂联合进行临床试验。然而，哪些患者最有可能受益于FAK抑制剂，以及最佳FAK/免疫治疗组合是什么，目前尚不清楚。我们鉴定了T细胞共刺激配体CD 80的癌细胞表达使鼠肿瘤对FAK抑制剂敏感，并且表明CD 80由源自实体上皮癌和一些血液恶性肿瘤的人癌细胞表达，其中FAK抑制剂尚未进行临床测试。在不存在CD 80的情况下，我们确定靶向替代性T细胞共刺激受体，特别是OX-40和4-1BB与FAK的组合，可以驱动增强的抗肿瘤免疫，甚至完全消退鼠肿瘤。我们的研究结果提供了支持FAK抑制剂与基于癌细胞CD 80表达的患者选择相结合的临床开发的理论基础，或者与靶向T细胞共刺激途径的疗法相结合。
Focal Adhesion Kinase (FAK) inhibitors are currently undergoing clinical testing in combination with anti-PD-1 immune checkpoint inhibitors. However, which patients are most likely to benefit from FAK inhibitors, and what the optimal FAK/immunotherapy combinations are, is currently unknown. We identify that cancer cell expression of the T-cell co-stimulatory ligand CD80 sensitizes murine tumors to a FAK inhibitor and show that CD80 is expressed by human cancer cells originating from both solid epithelial cancers and some hematological malignancies in which FAK inhibitors have not been tested clinically. In the absence of CD80, we identify that targeting alternative T-cell co-stimulatory receptors, in particular OX-40 and 4-1BB in combination with FAK, can drive enhanced anti-tumor immunity and even complete regression of murine tumors. Our findings provide rationale supporting the clinical development of FAK inhibitors in combination with patient selection based on cancer cell CD80 expression, and alternatively with therapies targeting T-cell co-stimulatory pathways.