Department of Pathology, Yale School of Medicine, New Haven, CT, 06510, USA.
Yale Cancer Center, Yale School of Medicine, New Haven, CT, 06510, USA.
J Immunother Cancer. 2019 Jul 23;7(1):194. doi: 10.1186/s40425-019-0675-0.
The cancer-associated fibroblast (CAF) population is implicated in immune dysregulation. Here, we test the hypothesis that CAF profiles in pretreatment tumor specimens are associated with response to immune checkpoint blockade of programmed cell death 1 (PD-1).
Pretreatment whole tissue sections from 117 melanoma patients treated with anti-PD-1 therapy were assessed by multiplex immunofluorescence to detect CAFs defined by Thy1, smooth muscle actin (SMA), and fibroblast activation protein (FAP). Two independent image analysis technologies were used: inForm software (PerkinElmer) to quantify cell counts, and AQUA™ to measure protein by quantitative immunofluorescence (QIF). CAF parameters by both methodologies were assessed for association with previously measured immune markers (CD3, CD4, CD8, CD20, CD68, PD-L1), best overall response, progression-free survival (PFS), and overall survival (OS).
CAF parameters, by cell counts or QIF, did not correlate with immune markers nor with best overall response. However, both Thy1 and FAP cell counts had significant positive associations with PFS (all P < 0.05) and OS (all P < 0.003). SMA cell counts showed negative associations with outcome in anti-PD-1 treated patients. Similar associations were not observed in a control cohort of historical melanoma patients predating immunotherapy. Instead, FAP was a negative prognostic biomarker (P = 0.01) in the absence of immunotherapy. Multivariable analyses revealed significant PFS and OS associations with the CAF parameters were independent of baseline variables.
Pretreatment CAF profiles are associated with melanoma immunotherapy outcome. Multiplex CAF analysis has potential as an objective companion diagnostic in immuno-oncology.
癌症相关成纤维细胞（CAF）群与免疫失调有关。在这里，我们检验了这样一个假设，即在接受 PD-1 免疫检查点阻断治疗的黑素瘤患者的预处理肿瘤标本中，CAF 特征与对免疫检查点阻断的反应有关。
通过多色免疫荧光法检测 117 例接受抗 PD-1 治疗的黑素瘤患者的预处理全组织切片，以检测由 Thy1、平滑肌肌动蛋白（SMA）和成纤维细胞激活蛋白（FAP）定义的 CAF。使用两种独立的图像分析技术：InForm 软件（PerkinElmer）用于量化细胞计数，AQUA™用于通过定量免疫荧光法（QIF）测量蛋白质。通过这两种方法评估 CAF 参数与以前测量的免疫标志物（CD3、CD4、CD8、CD20、CD68、PD-L1）、最佳总体反应、无进展生存期（PFS）和总生存期（OS）之间的相关性。
CAF 参数，通过细胞计数或 QIF，与免疫标志物或最佳总体反应均无相关性。然而，Thy1 和 FAP 细胞计数与 PFS（均 P < 0.05）和 OS（均 P < 0.003）均有显著的正相关。SMA 细胞计数与抗 PD-1 治疗患者的结果呈负相关。在免疫治疗前的历史黑素瘤患者的对照队列中未观察到类似的相关性。相反，在没有免疫治疗的情况下，FAP 是一个负预后生物标志物（P = 0.01）。多变量分析显示，与 CAF 参数相关的 PFS 和 OS 显著相关，独立于基线变量。
预处理 CAF 特征与黑素瘤免疫治疗结果相关。多重 CAF 分析有可能成为免疫肿瘤学中的一种客观伴随诊断。
