Moreno-Ruiz Pablo, Corvigno Sara, Te Grootenhuis Nienke C, La Fleur Linnéa, Backman Max, Strell Carina, Mezheyeuski Artur, Hoelzlwimmer Gabriele, Klein Christian, Botling Johan, Micke Patrick, Östman Arne
Karolinska Institutet, Cancer Center Karolinska, Department of Oncology-Pathology, Stockholm, Sweden.
Karolinska Institutet, Cancer Center Karolinska, Department of Oncology-Pathology, Stockholm, Sweden; Uppsala University, Genetics and Pathology, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden.
Lung Cancer. 2021 May;155:10-19. doi: 10.1016/j.lungcan.2021.02.028. Epub 2021 Feb 25.
Fibroblasts regulate tumor growth and immune surveillance. Here, we study FAP, PDGFβR and α-SMA fibroblast markers in a well-annotated clinical cohort of non-small-cell lung cancer (NSCLC) for analyses of associations with immune cell infiltration, mutation status and survival.
A well-annotated NSCLC cohort was subjected to IHC analyses of stromal expression of FAP, PDGFβR and α-SMA and of stromal CD8 density. Fibroblast markers-related measurements were analyzed with regard to potential associations with CD8 density, cancer genetic driver mutations, survival and PD-L1 expression in the whole NSCLC cohort and in subsets of patients.
High stromal FAP expression was identified as an independent poor prognostic marker in the whole study population (HR 1.481; 95 % CI, 1.012-2.167, p = 0.023) and in the histological subset of adenocarcinoma (HR 1.720; 95 % CI, 1.126-2.627, p = 0.012). Among patients with adenocarcinoma, a particularly strong association of FAP with poor survival was detected in patients with low stromal CD8 infiltration, and in other subpopulations identified by specific clinical characteristics; elderly patients, females, non-smokers and patients with normal ECOG performance status. α-SMA expression was negatively associated with CD8 infiltration in non-smokers, but none of the fibroblast markers expression was associated with CD8 density in the whole study population. Significant associations were detected between presence of p53 mutations and high α-SMA (p = 0.003) and FAP expression (p < 0.001).
The study identifies FAP intensity as a candidate independent NSCLC prognostic biomarker. The study also suggests continued analyses of the relationships between genetic driver mutations and the composition of tumor stroma, as well as continued probing of marker-defined fibroblasts as NSCLC subset-specific modifiers of immune surveillance and outcome.
成纤维细胞可调节肿瘤生长和免疫监视。在此，我们在一个注释完善的非小细胞肺癌（NSCLC）临床队列中研究FAP、PDGFβR和α-SMA成纤维细胞标志物，以分析其与免疫细胞浸润、突变状态和生存的相关性。
对一个注释完善的NSCLC队列进行免疫组化分析，检测FAP、PDGFβR和α-SMA的基质表达以及基质CD8密度。分析成纤维细胞标志物相关测量结果与整个NSCLC队列及患者亚组中CD8密度、癌症基因驱动突变、生存和PD-L1表达的潜在关联。
在整个研究人群中（HR 1.481；95%CI，1.012 - 2.167，p = 0.023）以及腺癌组织学亚组中（HR 1.720；95%CI，1.126 - 2.627，p = 0.012），高基质FAP表达被确定为独立的不良预后标志物。在腺癌患者中，在基质CD8浸润低的患者以及由特定临床特征确定的其他亚组中，检测到FAP与不良生存之间存在特别强的关联；老年患者、女性、不吸烟者以及ECOG体能状态正常的患者。在不吸烟者中，α-SMA表达与CD8浸润呈负相关，但在整个研究人群中，没有一种成纤维细胞标志物表达与CD8密度相关。在p53突变的存在与高α-SMA（p = 0.003）和FAP表达（p < 0.001）之间检测到显著关联。
该研究将FAP强度确定为候选的独立NSCLC预后生物标志物。该研究还建议继续分析基因驱动突变与肿瘤基质组成之间的关系，以及继续探究作为免疫监视和结果的NSCLC亚组特异性调节因子的标志物定义的成纤维细胞。
