Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA.
Cancer Immunology Discovery, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92021, USA.
Cell Rep. 2020 Jul 7;32(1):107873. doi: 10.1016/j.celrep.2020.107873.
The tumor microenvironment is rich with immune-suppressive macrophages that are associated with cancer progression and resistance to immune checkpoint therapy. Using pre-treatment tumor biopsies complemented with single-cell RNA sequencing (RNA-seq), we characterize intratumoral immune heterogeneity to unveil potential mechanisms of resistance to avelumab (anti-PD-L1). We identify a proinflammatory F480MHCIILy6C macrophage population that is associated with response rather than resistance to avelumab. These macrophages are the primary source of the interferon-inducible chemokine Cxcl9, which facilitates the recruitment of protective Cxcr3 T cells. Consequently, the efficacy of avelumab in mouse tumor models is dependent on Cxcr3 and Cxcl9, and baseline levels of Cxcl9 in patients treated with avelumab are associated with clinical response and overall survival. These data suggest that, within the broadly immune-suppressive macrophage compartment, a pro-inflammatory population exists that promotes responsiveness to PD-L1 blockade.
肿瘤微环境富含具有免疫抑制作用的巨噬细胞，这些细胞与癌症进展和对免疫检查点治疗的耐药性有关。我们使用预处理的肿瘤活检样本，并结合单细胞 RNA 测序（RNA-seq），对肿瘤内免疫异质性进行了特征分析，以揭示对avelumab（抗 PD-L1）耐药的潜在机制。我们发现了一种促炎的 F480MHCIILy6C 巨噬细胞群体，它与avelumab 的反应而不是耐药性有关。这些巨噬细胞是干扰素诱导的趋化因子 Cxcl9 的主要来源，Cxcl9 有助于保护性 Cxcr3 T 细胞的募集。因此，avelumab 在小鼠肿瘤模型中的疗效依赖于 Cxcr3 和 Cxcl9，并且接受 avelumab 治疗的患者的 Cxcl9 基线水平与临床反应和总生存期相关。这些数据表明，在广泛的免疫抑制性巨噬细胞群中，存在一种促炎群体，它促进了对 PD-L1 阻断的反应性。
