The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy
The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy
复制标题
局部免疫格局决定肿瘤 PD-L1 异质性和对治疗的敏感性
DOI：
10.1172/jci127726
复制
发表时间：
2019-08-01
影响因子：
15.9
通讯作者：
Kuang, Dong-Ming
中科院分区：
文献类型：
--
作者：
Wei, Yuan;Zhao, Qiyi;Kuang, Dong-Ming
程序性死亡-1受体配体1（PD-L1）是侵袭性癌症中有希望的治疗靶点。然而，人类PD-L1（+）肿瘤的免疫景观和癌症特征及其在确定治疗效果中的作用尚不清楚。在本文中，我们对32种人类癌症的9769例患者的基因数据进行了详细研究，结果表明PD-L1不能完全代表IFN-γ特征，并可能代表肿瘤中的促炎性骨髓反应。局部免疫景观赋予的PD-L1异质性控制了患者的癌症特征和临床结局。从机制上讲，由巨噬细胞炎症反应引发的NF-κ B信号产生的PD-L1（+）癌细胞表现出积极存活、支持血管生成和转移的能力，而由活化的T细胞触发的STAT 1信号诱导PD-L1（+）癌细胞抵抗凋亡。重要的是，由巨噬细胞产生的PD-L1（+）癌细胞对常规化疗、肿瘤特异性效应T细胞的细胞毒性和免疫检查点阻断疗法具有很强的抵抗力。将免疫检查点阻断与体内巨噬细胞耗竭或NF-κ B抑制相结合的治疗策略有效且成功地引起癌症消退。我们的研究结果提供了对PD-L1（+）肿瘤功能特征的深入了解，并表明影响炎症细胞功能活动的策略可能有利于免疫检查点阻断治疗。
Programmed death-1 receptor ligand 1 (PD-L1) is a promising therapeutic target in aggressive cancers. However, immune landscapes and cancer hallmarks of human PD-L1(+) tumors as well as their roles in determining therapeutic efficacies are unknown. Here, we showed, in detailed studies of gene data regarding 9769 patients of 32 types of human cancers, that PD-L1 could not exclusively represent the IFN-gamma signature and potentially signified proinflammatory myeloid responses in a tumor. PD-L1 heterogeneity endowed by local immune landscapes controlled cancer hallmarks and clinical outcomes of patients. Mechanically, NF-kappa B signal elicited by macrophage inflammatory responses generated PD-L1(+) cancer cells exhibiting capabilities to aggressively survive, support angiogenesis, and metastasize, whereas STAT1 signal triggered by activated T cells induced PD-L1(+) cancer cells susceptive to apoptosis. Importantly, PD-L1(+) cancer cells generated by macrophages established great resistance to conventional chemotherapy, cytotoxicity of tumor-specific effector T cells, and therapy of immune-checkpoint blockade. Therapeutic strategy combining immune-checkpoint blockade with macrophage depletion or NF-kappa B inhibition in vivo effectively and successfully elicited cancer regression. Our results provide insight into the functional features of PD-L1(+) tumors and suggest that strategies to influence functional activities of inflammatory cells may benefit immune-checkpoint blockade therapy.