Mangia Anita, Saponaro Concetta, Vagheggini Alessandro, Opinto Giuseppina, Centonze Matteo, Vicenti Chiara, Popescu Ondina, Pastena Maria, Giotta Francesco, Silvestris Nicola
Functional Biomorphology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.
Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola (FC), Italy.
Cancers (Basel). 2019 Sep 18;11(9):1393. doi: 10.3390/cancers11091393.
Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) and forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR, and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), breast cancer type 1 susceptibility protein (BRCA1), poly (ADP-Ribose) polymerase 1 (PARP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS; = 0.045). A Kaplan-Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs ( = 0.037), and the phenotypes TILs-/AR+ and TILs-/FOXA1- had a worse DFS ( = 0.032, = 0.001 respectively). AR was associated with FOXA1 expression ( = 0.007), and the tumors FOXA1+ presented low levels of TILs ( = 0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs ( = 0.0117). Low TILs score was associated with poor patients' survival, and TILs level in combination with AR or FOXA1 expression affected patient's clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.
肿瘤浸润淋巴细胞（TILs）是免疫微环境的一个重要指标，在新型抗癌药物中发挥着核心作用。TILs在三阴性乳腺癌（TNBC）中具有很强的预后作用。关于其与雄激素受体（AR）和叉头框A1（FOXA1）的相互作用知之甚少。我们分析了TNBC患者中TIL水平、AR和FOXA1表达之间的关系及其临床意义。此外，我们还研究了它们与其他生物标志物如程序性细胞死亡配体-1（PD-L1）、乳腺癌1型易感蛋白（BRCA1）、聚（ADP-核糖）聚合酶1（PARP1）和Na+/H+交换调节因子1（NHERF1）的相互作用。通过免疫组织化学对124例TNBC样本中的蛋白质表达进行评估。TILs的检测遵循国际TILs工作组2014年的标准。Cox比例风险模型也用于识别与预后不良相关的危险因素。多因素分析确定TILs是无病生存期（DFS；P = 0.045）的独立预后因素。Kaplan-Meier分析显示，与低TILs患者相比，高TILs患者的DFS更好（P = 0.037），TILs-/AR+和TILs-/FOXA1-表型的DFS更差（分别为P = 0.032和P = 0.001）。AR与FOXA1表达相关（P = 0.007），FOXA1+的肿瘤TILs水平较低（P = 0.028）。与其他TNBC相比，AR+/FOXA1+肿瘤的DFS较差（P = 0.0117）。低TILs评分与患者生存率低相关，TILs水平与AR或FOXA1表达相结合会影响患者的临床结局。此外，AR+/FOXA1+表型确定了TNBC患者中一个预后不良的特定亚组。这些数据可能提示支持当前治疗的新的治疗干预方法。
