Department of Medecine, Institut Bergonié, Bordeaux, France.
Faculty of Medecine, University of Bordeaux, Bordeaux, France.
J Immunother Cancer. 2022 May;10(5). doi: 10.1136/jitc-2021-003890.
Tumor-associated macrophages (TAMs) having immunosuppressive properties are one of the most abundant immune cells in the tumor microenvironment (TME). Preclinical studies have highlighted the potential role of TAMs in resistance to immune checkpoint blockers (ICBs). Here, we investigated the predictive value of TAM infiltration in patients with non-small cell lung cancer (NSCLC) treated with ICBs and characterized their transcriptomic profiles.
Tumor samples were collected from 152 patients with NSCLC before ICB treatment onset. After immunohistochemical staining and image analysis, the correlation between CD163+ cell infiltration and survival was analyzed. Spatial transcriptomic analyses were performed using the NanoString GeoMx Immune Pathways assay to compare the gene expression profile of tumors with high or low levels of CD163+ cell infiltration and to identify determinants of response to ICBs in tumors with high CD163+ infiltration.
Low intratumoral CD163+ cell infiltration was associated with longer progression-free survival (PFS; HR 0.61, 95% CI 0.40 to 0.94, p=0.023) and overall survival (OS; HR 0.48, 95% CI 0.28 to 0.80, p=0.004) under ICB treatment. Spatial transcriptomic profiles of 16 tumors revealed the upregulation of , CD27, and in tumors with high CD163+ cell infiltration. Moreover, in tumors with high macrophage infiltration, the upregulation of genes associated with the interferon-γ signaling pathway and the M1 phenotype was associated with better responses under immunotherapy. Surprisingly, we found also a significantly higher expression of in the tumors of responders. Analysis of three independent data sets confirmed that high expression was associated with an increased durable clinical benefit rate (47% vs 6%, p=0.004), PFS (median 10.89 months vs 1.67 months, p=0.001), and OS (median 23.11 months vs 2.66 months, p<0.001) under ICB treatment.
Enrichment of TAMs in the TME of NSCLC is associated with resistance to immunotherapy regardless of the programmed death ligand 1 status and is driven by upregulation of , and gene expression within the tumor compartment. Our transcriptomic analyses identify new potential targets to alter TAM recruitment/polarization and highlight the complexity of the CSF1R pathway, which may not be a suitable target to improve ICB efficacy.
肿瘤相关巨噬细胞（TAMs）具有免疫抑制特性，是肿瘤微环境（TME）中最丰富的免疫细胞之一。临床前研究强调了 TAMs 在抵抗免疫检查点抑制剂（ICBs）中的潜在作用。在这里，我们研究了 TAM 浸润在接受 ICB 治疗的非小细胞肺癌（NSCLC）患者中的预测价值，并对其转录组谱进行了表征。
在 ICB 治疗开始前，收集了 152 名 NSCLC 患者的肿瘤样本。进行免疫组织化学染色和图像分析后，分析了 CD163+细胞浸润与生存之间的相关性。使用 NanoString GeoMx 免疫途径检测试剂盒进行空间转录组分析，以比较 CD163+细胞浸润水平高或低的肿瘤的基因表达谱，并确定 CD163+浸润水平高的肿瘤对 ICB 反应的决定因素。
低肿瘤内 CD163+细胞浸润与更长的无进展生存期（PFS；HR 0.61，95%CI 0.40 至 0.94，p=0.023）和总生存期（OS；HR 0.48，95%CI 0.28 至 0.80，p=0.004）相关。16 个肿瘤的空间转录组谱显示，在 CD163+细胞浸润水平高的肿瘤中， 、CD27 和 上调。此外，在巨噬细胞浸润水平高的肿瘤中，与干扰素-γ信号通路和 M1 表型相关的基因上调与免疫治疗下更好的反应相关。令人惊讶的是，我们还发现反应者的肿瘤中 表达显著升高。对三个独立数据集的分析证实，高 表达与增加持久临床获益率（47% vs 6%，p=0.004）、PFS（中位 10.89 个月 vs 1.67 个月，p=0.001）和 OS（中位 23.11 个月 vs 2.66 个月，p<0.001）相关。
NSCLC 的 TME 中 TAMs 的富集与免疫治疗的耐药性有关，无论程序性死亡配体 1 状态如何，这是由肿瘤内 、 和 基因表达的上调驱动的。我们的转录组分析确定了改变 TAM 募集/极化的新潜在靶点，并强调了 CSF1R 途径的复杂性，该途径可能不是提高 ICB 疗效的合适靶点。
