Abstract
ObjectivesFibroblasts 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. Materials and MethodsA 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. ResultsHigh 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). ConclusionThe 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.
Highlights
Experimental studies suggest that cancer-associated fibroblasts (CAFs) can affect the outcome of non-small lung cancer (NSCLC) by regulating e.g., proliferation, survival and metastatic potential [1,2,3] of malignant cells as well as by influencing angiogenesis [4] and immune surveillance [5]
Analyses on possible relationships between fibroblast status and CD8+ cells infiltration in the whole study population failed to detect strong associations. These findings are similar to an earlier study reporting Spearman correlation values below 0.2 for CD8 and the three fibroblast markers in a population of unselected stage IA-IIIA non–small-cell lung cancer (NSCLC) patients [33]
The present study identifies a set of subset-specific association between CAF subtypes and features such as immune cells infiltration and cancer cell driver mutations as P53, which merit further experimental exploration
Summary
A series of recent studies have high-lighted the existence of clinically relevant differences in the composition of the stroma compartment of common solid tumors [6]. These differences have been found to impact both the natural course of the disease as well as response to treatment. Some of these studies, performed in NSCLC and indicate prognostic impact of certain marker-defined fibroblast subsets [7,8,9]. Used fibroblast markers for characterization of clinical.
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