Tissue analyses reveal a potential immune-adjuvant function of FAP-1 positive fibroblasts in non-small cell lung cancer

ObjectivesSelective targeting of cancer-associated fibroblasts (CAFs) has been proposed to synergize with immune-checkpoint inhibitors. While the roles of CAFs in cancer development are well described, their immune-regulatory properties remain incompletely understood. This study investigates correlations between CAF and immune-markers in tumor stroma from non-small cell lung cancer (NSCLC) patients, and examines whether a combination of CAF and immune cell scores impact patient prognosis.MethodsTumor specimens from 536 primary operable stage I-III NSCLC patients were organized in tissue microarrays. Expression of protein-markers was evaluated by immunohistochemistry.ResultsFibroblast and stromal markers PDGFRα, PDGFRβ, FAP-1 and vimentin showed weak correlations while αSMA, and Masson’s trichrome did not correlate with any of the investigated markers. Hierarchical clustering indicated the existence of different CAF-subsets. No relevant correlations were found between any CAF-marker and the immune-markers CD3, CD4, CD8, CD20, CD68, CD1a, CD56, FoxP3 and CD45RO. High density of fibroblast-activation protein positive mesenchymal cells (CAFFAP) was associated with better prognosis in tumors with high infiltration of CD8 and CD3 T-lymphocytes.ConclusionsThe presented data suggest that CAFs, irrespective of identity, have low influence on the degree of tumor infiltration by inflammatory- and/or immune-cells. However, CAFFAP may exert immuno-adjuvant roles in NSCLC, and targeting CAFs should be cautiously considered.研究背景与目的：靶向癌症相关成纤维细胞（cancer-associated fibroblasts, CAFs）已被提出可与免疫检查点抑制剂（immune-checkpoint inhibitors）发挥协同抗肿瘤作用。尽管CAFs在癌症发生发展中的作用已得到充分阐释，但其免疫调控特性仍未被完全阐明。本研究旨在探究非小细胞肺癌（non-small cell lung cancer, NSCLC）患者肿瘤间质中CAFs与免疫标志物的相关性，并分析CAFs评分与免疫细胞评分的联合应用是否会对患者预后产生影响。 方法：本研究纳入536例可手术切除的I-III期原发性NSCLC患者的肿瘤标本，制备为组织微阵列（tissue microarrays）；采用免疫组织化学（immunohistochemistry）法检测相关蛋白标志物的表达水平。 结果：成纤维细胞及间质标志物PDGFRα、PDGFRβ、FAP-1与波形蛋白（vimentin）仅呈现弱相关性，而αSMA及马松三色染色结果与所有检测标志物均无相关性。层级聚类分析（hierarchical clustering）显示存在不同的CAFs亚群。所有CAFs标志物与CD3、CD4、CD8、CD20、CD68、CD1a、CD56、FoxP3及CD45RO等免疫标志物均未发现显著相关性。在CD8与CD3 T淋巴细胞高浸润的肿瘤中，成纤维细胞活化蛋白阳性间质细胞（CAFFAP）高密度与更好的患者预后相关。 结论：本研究数据表明，无论CAFs的亚型如何，其对肿瘤组织内炎症细胞和/或免疫细胞的浸润程度均影响较小。然而，CAFFAP在NSCLC中可能发挥免疫佐剂样作用，因此靶向CAFs的治疗策略需谨慎评估。